Genetics Final Exam Super-Set
where is the BCKDHA gene located? (MSUD)
-19q13.1-q13.2
initiation codon
-ATG
45, X
-Turner's syndrome
inheritance of hemophilia B
-X-linked -more often seen in males
what did the US National Intelligence report call genome editing?
-a weapon of mass destruction and proliferation
dysplasia
-abnormal organization of normal cells
how many genes does the human genome contain?
-about 25,000 genes, composing about 5% of the total DNA within the nucleus
copper
-absorbed in the stomach-duodenum from enterocytes -transported to liver, bound to albumin -used in a step of ceruloplasmin formation (carries copper; iron metabolism; neuronal maintenance)
pharmacokinetics
-actions of the body that change the physical and chemical properties of a drug -drug absorption, metabolism, elimination
homogenous
-alleles are the same, whether dominant or recessive
how much does each FISH probe cost?
-around $200 -multiple probes are used to screen patients for several conditions
how is cystic fibrosis manifested?
-as pulmonary, GI, and reproductive problems, and elevated chloride in sweat (>60 mEq/L)
missense mutation
-bases changes that result in an AA change -may or may not be deletious -Glu6Val means that the normal amino acid at site #6 is glutamine but has been replaced with valine due to the mutation
compound heterozygote- familial hypercholesterolemia
-carries 2 different recessive allele mutations -more severe form
most common mutation that leads to cystic fibrosis
-caused by an in-frame 3-bp deletion (termed △F508) -causes omission of a single phenylalanine at amino acid 508
cause of retinoblastoma
-caused by inactivation of RB1 gene: 13q14.3
mitosis
-cell division in which there is a duplication of a parent cell resulting in two new daughter cells that are identical to each other and to the parent cell
somatic mutation
-cells of body affected -mutations can occur early or late in development -portion of body maintains mutation
treatment of retinoblastoma
-cryotherapy, laser, chemo, radiation -if possible, any radiation should be avoided in gremlin retinoblastoma to minimize lifetime risk of developing late-onset second cancers
what disease is known for clinical variability?
-cystic fibrosis -caused by a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR)
example of an in-frame mutation
-cystic fibrosis -normal chloride channels: Ile- Ile- Phe- Gly- Val 506 507 508 509 510 -chloride channels that lead to cystic fibrosis (70% of cases): Ile- Ile- Gly- Val 506 507 509 510
where is the GALK1 gene located?
-cytogenic- 17q24 -molecular location on chromosome 17- base pairs 75,757,936 to 75,765,198
Potter facies
-deformation sequence of oligohydramnios presents as this -characterized by hypertelorism, low-set ears, receding chin, tapering fingers, and infraorbital folds
Thalassemias
-fatal blood disorders associated with a marked suppression or absence of hemoglobin production
tissue-specific genes
-genes expressed only in specific tissues -can be expressed differentially or constitutively
nondisjunction
-gives you extra chromosomes -happens during meiosis -causes trisomies
constant allele frequencies
-hardy-weinberg equilibrium
trisomic cell
-has a complete chromosome complement plus a single extra chromosome
when is it acceptable to disclose private health information according to IOM and presidential commission?
-if it is very likely that harm will result if the information is not disclosed -when harm from not disclosing the information would be greater than the harm of disclosing the information
type 2 collagen
-in cartilage
hemolytic anemia
-lack of red blood cells
CYP2D6 level in poor metabolizers? intermediate? extensive? ultra-rapid?
-none -low -normal -high
proto-oncogene
-normally inherited -required for normal cell function
where is the majority of the cell's DNA found?
-nucleus
difference between multifactorial and polygenic diseases
-polygenic- multiple genes involved in the disease; has nothing to do with the environment -multifactorial- has to do with the environment -could be both, not always
behavioral and lifestyle mutagens- risk factors
-poor diet -lack of physical activity -weight -smoking -not getting recommended screening tests
deformation sequence of renal agenesis
-presents as Potter facies, characterized by hypertelorism, low-set ears, receding chin, tapering fingers, and infraorbital folds
rapid FISH panel
-probes directed at 13, 18, 21, X and Y -allows for 24 hour diagnosis
is sickle cell dominant or recessive?
-recessive
silencers
-repress transcription
variants of unknown significance (VUS)
-something is abnormal but we do not know what it is or what it does -do not have a disease connected to it but it is different from normal population
Polymerase Chain Reaction Testing (PCR)
-specific dan sequences are copied many times to yield large quantities of that particular DNA portion corresponding to a certain gene -provides exact repeat number -need to know what area to amplify
Becker Muscular Dystrophy
-starts in adolescence -often live a little longer- into 30s
management of PKU
-strict dietary restriction of phenylalanine intake (less than 300-500 mg daily) -drug therapy- sapropterin (Kuvan)
genetics
-study of individual genes and inheritance
what does it mean if a gene is constitutively expressed?
-the gene is expressed continually
founder effect
-the genetic impact of starting a new population from a relatively small group of individuals
histones
-tightly packed proteins that regulate gene expression (ex- protein production that allows bodies to function normally) -equipped with chemical tags that serve as switches -DNA spools around it to fit inside cell
what tissues does mitochondrial inheritance effect?
-tissues with greatest energy demands
signs and symptoms of factor V leiden
-venous thrombotic clots, pulmonary emboli, arterial clots -stillbirths, recurrent miscarriages, preeclampsia, eclampsia
what is the risk in males for fragile X tremor ataxia syndrome related to?
0age
disorders caused by problem in type 1 collagen
=osteogenesis -ehlers-danlos syndrome
which form of OI is the most clinically variable?
type IV
cost of PCR testing
-$300-500
how much does karyotype-cytogenetic testing cost? when do you get the result? what is the exception?
-$450 -10-14 days -CVS where rapid result is needed
penetrance
-% of individuals of a specific genotype showing the expected phenotype -on a population level
incidence of renal agenesis
-0.4 to 3.9 in 10,000 births for bilateral -0.4-4.9 in 10,000 births for unilateral agenesis
how much filtered cystine normally appears in the urine?
-0.4%
how many caucasians are carriers of cystic fibrosis?
-1 in 22 to 28
incidence of marfan syndrome
-1 in 5000 live births
incidence of hemophilia B
-1/7 of hemophilia A
how many black males have G6PD Deficiency?
-10%
what percentage of breast and ovarian cancers are attributed to germ line?
-10% -appears autosomal dominant
gene amplification leading to an oncogene
-10% of tumors -detected at later stages of cancer
what percentage of cancers are familial cancers?
-10-15%
how many genes are known to be associated with long QT syndrome
-12
cytochrome P450
-12 enzyme families -each encoded by a different CYP gene (about 51 genes) -includes about 50 enzymes that metabolize more than 30 classes of drugs -6 genes in particular encode the enzymes responsible for 90% of all commonly used drugs
DAO and DAOA- schizophrenia
-12q24 and 13q34- interact together -exact function is unknown- involved in glutamate receptor activation -4 SNPs are associated with schizophrenia in case controlled studies
mucopolysaccharidoses- lysosomal storage disorders
-14 known types that affect degradation of glycosaminoglycan (GAG), an important constituent of extracellular matrix, joint fluid, and connective tissue -types include heparan sulfate and derma tan sulfate
fragile X testing
-1991- DNA test 99% accurate -examines FMR1 gene (Xq27.3) -costs $300-$500 -results in 2-4 weeks -PCR
incidence of congenital adrenal hyperplasias
-1:10,000 to 1:20,000 births
incidence of retinoblastoma
-1:20,000
prevalence of cystic fibrosis
-1:2000 infants born with recessive disorder -30,000 affected individuals in US -blacks (1:15,000) and Asian Americans (1:31,000) are rarely affected
incidence of DMD
-1:3600 live male births
incidence of heterozygous familial hypercholesterolemia
-1:500
incidence of sickle cell disease
-1:500 US AA Children -1:15 AA Carrier status
incidence of sickle cell disease
-1:500 US AA children 1:15 AA carrier status
incidence of ehlers-danlos syndrome
-1:5000
incidence of hemophilia A
-1:5000 live male births
incidence of long QT syndrome
-1:7000
prevalence of familial adenomatous polyposis (FAP)? what percentage of colorectal cancers are FAP? is it dominant or recessive? what is the penetrance?
-1:8000 -1-5% of colorectal cancers -autosomal dominant -almost 100%
where is the DBT gene located? (MSUD)
-1p31
moderate risk- family history risk assessment for complex cardiac diseases
-1st degree relative with late or unknown disease onset -two 2nd degree relatives from same lineage with late or unknown disease onset
how many hydrogen bonds does adenine form with thymine?
-2
heterozygous
-2 different alleles
homozygous
-2 of the same alleles
genomics of retinoblastoma
-2 separate mutations are necessary for tumor development -one may be present in gremlin- in every somatic cell and passed into subsequent generations -second mutation would be somatic and within the retinal cells -this eliminates the protein of both alleles
what percentage of individuals in Europe and North America develop colorectal cancers? what percentage of colorectal cancers are familial?
-2% -30%- familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer
Fragile X primary ovarian insufficiency
-22% of females with permutation -spectrum of ovarian dysfunction- irregular or absent periods, reduced fertility, premature or early menopause
what is the chance that a child will have two normal genes if both parents are carriers of the autosomal recessive disease? carrier? have the disease?
-25% -50% -25%
what is the chance that an offspring will be affected by a disease if both parents are carriers of the recessive gene?
-25% chance of normal -50% chance of carrier -25% chance they will have it
heterozygous familial hypercholesterolemia
-2nd most common single gene disorder -present from birth; asymptomatic until 30s or 40s
how many bases code for one amino acid?
-3
how many hydrogen bonds does guanine form with cytosine?
-3
what needs to be included during the collection step of family history
-3 generations -age or birth year of relatives -cardiac diseases and age of onset -risk factors (that increase cardiac risk) -age and cause of death
triploidy
-3 sets of chromosomes -extra copy of each chromosome, resulting in 69 chromosomes (23 x 3) -caused by fertilization of one ovum (23) by 2 sperm (23 + 23)
what is the life expectancy of someone with menses syndrome?
-3-10 years
Safer vs. Estate
-30 years after her father died, woman sued the estate of her father's physician for failing to warn her of risk for familial adenomatous polyposis -telling patient to tell family is not enough -must take reasonable steps to assure that risk is communicated
what percent of DMD cases are caused by duplication, point mutations, small insertions, or deletions?
-30%
what does it mean if you have a parental family history of ischemic stroke <65 years?
-300% increase in risk in offspring
Romano Ward caused by LQT2
-35% of cases -mutations in KCNH2 gene on chromosome 7 -codes for a potassium ion channel required for repolarization -provoked by auditory stimuli
incidence of Jervell and Lange-Nielsen syndrome- LQT
-3:1 million
incidence and causes of JLN syndrome- long QT
-3:1 million -90% due to mutations in KCNQ1 gene -KCNE2 involved in 10%
how much does the risk for breast cancer increase when the person has a first degree relative with breast cancer? what if they have more than one first degree relative?
-3x higher -10x higher -family clustering with a multifactorial mechanism
what is DNA made of? what constitutes the DNA sequence of a gene and the code for the amino acid sequence of a protein?
-4 bases, called nucleotides -the order of the bases
tetraploidy
-4 sets of chromosomes -92 chromosomes
genomics of retinoblastoma
-40% are germinal (heritable) and can effect both eyes; 20% family history -60% non-germinal and usually effects one eye
how many triplet repeats present in adult onset huntington disease
-40-50 repeats
Turner syndrome
-45, X -one X chromosome instead of 2
what is chromatin organized into in each nucleus?
-46 chromosomes- 23 pairs -22 autosome pairs, one sex chromosome pair
what are the normal results for karyotype-cytogenetic testing? what are some conditions under which this test may be performed?
-46, XX or 46, XY -multiple birth defects, developmental delays, CML or other leukemias, ambiguous genitalia
klinefelters syndrome
-47, XXY
Jacobs syndrome
-47, XYY
male and female nondisjunction
-48, XXYY Syndrome
what percentage of cancer is inherited?
-5-10%
what percentage of cancers are hereditary?
-5-10%
chance that a daughter of a female who carries an x-linked recessive gene for a disease will be affected?
-50%
chance that a son of a female who carries an x-linked recessive gene for a disease will be affected?
-50%
how much does family history of stroke increase stroke risk by?
-50%
what is the chance that the offspring of parents where one has an X-linked dominant gene will be affected?
-50%
what chance does each offspring of a couple where one is affected by an autosomal dominant disease and one is not?
-50% chance of being affected
f there is a couple where the mother has an x-linked dominant trait for a disease and the father is unaffected, what are the chances that the sons or daughters of the couple will be affected?
-50% for sons -50% for daughters
ovarian cancer
-5th leading cause of death from cancer long women; most fatal cancer among women -5 year survival rate of <50% -mostly sporadic; 5-10% hereditary -BRCA1 (70%) and BRCA 2 (20%) mutations account for 90% of inherited ovarian cancer
what percent of DMD cases are caused by deletions? BMD?
-65% -85%
DTNBP1- schizophrenia
-6p22.3 -expression reduced in hippocampus resulting in decreased cognitive function
where is the BCKDHB gene located? (MSUD)
-6q14.1
incidence of OI
-7 per 100,000
what is the incidence of osteogenesis imperfect? what types are more common? is it dominant or recessive?
-7 per 100,000 -types I-IV -autosomal dominant
congenital heart disease- complex cardiac diseases
-7-12% have chromosome abnormality -polygenic -recurrence risk of 2-10% -altered levels of cardiogenesis proteins
what percentage of cancers are sporadic?
-75%
transmission of Marfan syndrome
-75% autosomal dominant transmission 25% de novo
where is the DLD gene located? (MSUD)
-7q31-q32
how much does a family history of Atrial fibrillation increase Afib risk by?
-80%
what is the lifetime risk for hereditary nonpolyposis colorectal cancer (HNPCC)? what is the mean age of onset?
-80% -44
what does 80% penetrance mean?
-80% of the people with the genotype will have the disease or phenotype
NRG1- schizophrenia
-8p21-22 -important for neuronal development, activation of neurotransmitter receptors, axon maintenance -in a more rare form of velocardiofacial syndrome, this area is deleted and up to 30% will develop schizophrenia
Trimodel activity- TPMT
-90%- high TPMT activity- faster drug metabolism -10%- intermediate activity -about 0.3%- low activity: reduced or nonfunctional protein, possibly fatal toxicity, chemo doses reduced 8-10 fold
trimodel activity- TPMT
-90&- high TPMT activity (faster drug metabolism) -10%- intermediate activity -0.3%- low activity- reduced or nonfunctional protein, possibly fatal toxicity, chemotherapy disease reduced 8-10 fold
2 mutations that 99% of individuals with achondroplasia have one of
-98% harbor G to A mutation at nucleotide 1138(G1138A); replaces glycine with an arginine at AA380 -1% have a G1138C that substitutes a cysteine for a glycine at the same nucleotide
gene associated with coronary heart disease
-9p21 -most consistently replicated SNP associated with heart disease -reclassified 6.8% of the sample from low risk to high risk
how many triplet repeats are present in juvenile huntington disease?
->60 CAG repeats
nonsense mutation
-A DNA base change can result in an amino acid being replaced by a stop codon -UGU to UGA (U to A mutation)
genetics of Factor V Leiden
-A to G missense mutation in the factor V coagulation factor gene on chromosome 1 -results in an arginine to glutamine substitution that causes factor V to be inactivated at a much slower rate -this mutation occurs in 95% of cases
Fabry disease- lysosomal storage disease
-A-galactosidase is inherited in an x-linked manner, mutations in associated GLA gene -substrate accumulation in endothelial cells, pericytes, smooth muscle, dorsal ganglia, myocardial cells, etc.
alzheimer disease susceptibility testing
-APOE genotype may be used to confirm diagnosis -testing for APOE4 allele is not conclusive for prediction; can be found in people without alzheimers -1st degree relatives have a lifetime risk of 20%-25%, which is 2.5x higher than background population
gene affected in Menkes syndrome
-ATP7A
gene and defect of Menkes syndrome
-ATP7A -intestinal absorption of copper
gene and defect in Wilsons disease
-ATP7B -Biliary excretion of copper
what is the start codon?
-AUG, which codes for methionine -when this codon is encountered within the mRNA sequence, it is considered the place to start building the amino acid chain
nucleotide bases in mRNA
-Adenine and uracil -guanine and cytosine
Fluorescence in Situ Hybridization (FISH)
-As banding techniques were improved, DNA segments could be fluorescently labeled (FISH Probes) -targeted micro-deletions and duplication regions as small as 100,000 base pairs -more than 40 DNA probes are used
management of long QT syndrome
-B-adrenergic blockers, such as propranolol and atenolol -LQT3, the Na channel defect, responds best to the Na channel blocker mexiletine -implantable cardioverter-defibrillator (ICD)
what gene is affected in sickle cell disease?
-B-globin gene 11p15.5 -B-globin protein 146 amino acid protein -A to T substitution, missense mutation
genetics of sickle cell disease
-B-globin gene 11p15.5 -autosomal recessive -B-globin protein 146 amino acid protein -a to T substitution, a missense mutation, results in sickled red blood cells
mutations in what genes cause maple sugar urine disease?
-BCKDHA- most common -BCKDHB -DBT -DLD
which gene increases the risk for breast and ovarian cancer the most if mutated?
-BRCA1
what genes most commonly cause breast cancer?
-BRCA1: 17q21 -BRCA2: 13q12
syndromes associated with multi cystic renal dysplasia
-Beckwith-Wiedemann syndrome -trisomy 18 -Waardenburg syndrome -Joubert syndrome -VACTERL (vertebral, anal, cardiac, tracheal, esophageal, renal, and limb) association
history of genetic discrimination
-Burlington Northern Santa Fe (BNSF) Railroad -woman with hemochromatosis lost health insurance, though no clinical disease (low penetrance) -family lost health insurance for their son with Fragile X syndrome -man denied employment because he possessed one copy of the allele that causes Gaucher disease (unaffected carrier)
gene that can cause cystic fibrosis
-CFTR gene -1500 mutations have been described
cause of cystic fibrosis
-CFTR gene located on the long arm of chromosome 7; large and contains 27 eons and 1480 amino acids -1500 different mutations have been described -most common is caused by in-frame 3-bp deletion (termed (F508)- causes omission of a single phenylalanine at amino acid 508
what is the difference between CMA and whole genome sequencing (WGS) genetic testing?
-CMA detects changes in gene dosage caused by micro deletions and microduplications -WGS identifies smaller variants in the "spelling" of genes
population phenotypes for CYP alleles
-CYP alleles can result in absent, decreased, or increased enzyme activity, thus affecting rate at which many drugs are metabolized
6 liver enzymes responsible for metabolism of 90% of all commonly used drugs
-CYP1A1 -CYP1A2 -CYP3A4 -CYP2C9 -CYP2C19 -CYP2D6
what reduces warfarin metabolism? by how much?
-CYP2C9*2 and CYP2C9*3 shown to reduce warfarin metabolism by about 30-50% and 90% respectively -commonly analyzed in commercial laboratories
what is responsible for metabolizing codeine into morphine>
-CYP2D6
what is not allowed/illegal under GINA?
-Cannot use genetic information to make decisions about eligibility, the size of their premiums, or the extent of their coverage -cannot use genetic information as evidence of a pre-existing condition -cannot require that a client have genetic testing -illegal for employers to use genetic information to make decisions about hiring, promotions, and termination of employment
what is hemophilia B also called?
-Christmas disease after first patient described with it
examples of deletion syndromes
-Cri du chat syndrome -Prader-Willi syndrome -angelman syndrome -DiGeorge syndrome -Smith-Magenis syndrome -Wold-Hirschhorn syndrome
normal function of caretaker gene
-DNA and chromosome stability
what is chromatin composed of?
-DNA and histone proteins
histone modification
-DNA is a very long structure that winds around histone proteins to condense -whether it is tight or loose has to do with how it is transcribed and translated -histones pack tightly together and regulate gene expression -equipped with chemical tags that serve as switches -done on purpose but can also cause disease
how does DNA looping affect enhancers and silencers?
-DNA looping brings proteins bound to remote enhancers or silencers into direct contact with proteins bound to the promoter
Fluorescence in Situ Hybridication test (FISH)
-DNA segments are fluorescently labeled -can detect targeted micro-delations and duplication regions as small as 100,000 base pairs -multiple FISH probes used to screen patients for several conditions -used only for specific disorders
testing for single gene disorders
-DNA sequencing -mutation analysis -PCR
candidate genes for schizophrenia
-DTNBP1 -NRG1 -DAO and DAOA
Trisomy disorders- chromosome mutations
-Down Syndrome (21) -Patau (13) -Edward's (18)
example of a nonsense mutation
-Duchenne muscular dystrophy
Human Genome Project and ELSI
-Ethical, Legal, and Social Implications research program -largest bioethics program in the world -financial issues also important- FELSI -human genome project set aside 3-5% of annual budget to study ELSI
genetics for Marfan Syndrome
-FBN1 gene is mutated- over 500 mutations, 70% missense -typically encodes fibrillin, a major structural component and forms elastic fibers -if mutated, microfibrils are unable to provide strength o all tissues, causing skeletal, ocular, and CV defects
testing for micro deletion or micro duplication syndromes
-FISH
what type of fragile X associated disorder is seen in females?
-FX Primary ovarian Insufficiency -number one cause of infertility -often have no major symptoms
what type of fragile X associated disorder is see in males more often?
-FX Tremor ataxia syndrome
T or F: A FMRP gene allele with greater than 200 CGG repeats is considered to be in the permutation category?
-False
who is cystinurea most common in?
-Founders effect -Libyan Jewish- 1:2500 -1:25 are carriers
fragile X associated disorders
-Fragile X syndrome -Fragile X Tremor Ataxia Syndrome -Fragile X Primary Ovarian Insufficiency
phases of cell division
-G1- cell takes on nutrients, generates more energy, increases membrane size and cytoplasm -S- DNA replication -G2- production of proteins important for cell division -M-actual cell division with nuclear separation (nucleokinesis) followed by cell separation (cytokinesis)
what is galactosemia caused by mutations in?
-GALE -GALK1 -GALT
what test can be done to detect Type I, II, and III hyperphenylalanemia (PKU)?
-Guthrie test or amino acid profiling of urine or plasma -fluorometric assay -tandem mass spectrometry
genetics of huntington disease
-HD repeat is found in the first exon of the gene loci 4p16.3 -results from the expansion of CAG triplet repeats -the number of CAG triplets normally present in the HTT (Huntington) gene is 10-26
what is involved in the Duty to Warn vs. the Right to Privacy argument?
-HIPAA requirements -beneficence -patient autonomy
what is involved in the duty to warn vs. the right to privacy?
-HIPAA requirements -beneficence -patient autonomy
what genes have a strong association to prostate cancers?
-HPC1 (1q24) -MSR1 (8p22)
what will children with retinoblastoma also have if it was caused by deletions in region of chromosome 13?
-ID -slow growth -distinctive facial features- prominent eyebrows, short nose, broad nasal bridge, ear abnormalities
symptoms of infant born from mother with maternal PKU
-IUGR -Microcephaly -heart abnormalities -intellectual disabilities
malformations in fetus of mother with maternal PKU
-IUGR -microcephaly -heart abnormalities -mental retardation
testing for hereditary nonpolyposis colorectal cancer
-Immunohistochemistry (IHC) staining- done to tumor tissue from individuals who fulfill Bethesda criteria to determine the presence or absence of MLH1, MSH2, MSH6, and PMS2 genes -MSI testing
male nondisjunction (meiosis 2)
-Jacobs syndrome -turner syndrome
LQT1 gene for Romano-Ward syndrome- LQT
-KCNQI gene on chromosome 11 -codes for potassium channel required for repolarization -triggered by exercise
what opthalmic finding is associated with Wilson disease?
-Kayser-Fleisher ring
treatment for homozygous familial hypercholesterolemia
-LDL apheresis -liver transplant -novel gene therapies
genetics of Long QT syndrome
-LQT syndrome is a genetically heterogenous and mechanistically complex disorder
what mutations cause Romano-Ward syndrome? Long QT
-LQT1- most common; >60% of cases -LQT2- 35% of cases -LQT3- less than 5% of cases -other forms are quite rare
genes associated with Romano-Ward syndrome- long QT syndrome
-LQT1: most common, >60% of cases -LQT2: 35% of cases -LQT3: <5% of cases -other forms are quite rare
what are mutations in the RET gene also responsible for? what is the inheritance?
-MEN type II cancer syndromes: MENIIA, MENIIB, and familial medullary thyroid carcinoma (FMTC) -all autosomal dominant
DNA repair genes that when mutated increase the risk of colon cancer and other cancers
-MSH2 -MSH6 -MLH1 -MLH3 hereditary mutations (germ line mutations) in any one of these genes has been associated with hereditary nonpolyposis colorectal cancer syndrome
gene locations that cause hereditary nonpolyposis colorectal cancer (HNPCC)
-MSH2: 2p22-21 and MLH1: 3p21.3 (90%) -PMS2: 7p22 (<5%) -MSH6: 2p16 (7-10%)
Preserving Employee Wellness Programs Act- 2017
-March 8, 2017- the house committee on education and the workforce approved a bill, H.R. 1313 (22 to 17 along party lines) -would allow employers to require employees to undergo genetic testing and share such information under a workplace wellness program -provides employers "the legal certainty they need to offer employee wellness plans, helping to promote a healthy workforce and lower health care costs"
side effects of imatinib Mesylate (Gleevec)- CML
-N/D -leg aches or cramps, swelling of face, altered bone marrow function -mild to moderate and usually in first month
types of genetic syndromes with cardiac involvement
-Noonan syndrome -Downs syndrome -Marfans syndrome
testing for triple repeat expansion mutations
-PCR -DNA testing for repeats -Methylation analysis
N-acetyltransferase (NAT)
-Phase II liver enzyme -adds an acetyl group onto drugs in the process of acetylation
forms of long QT syndrome
-Romano-Ward (RW) syndrome -Jervell and Lange-Nielsen (JLN) syndrome
genes associated with cystinurea
-SLC3A1 -SLC7A9
type 1 or A cystinurea
-SLC3A1 gene -normal urinary excretion -abnormal intestinal absorption
types II, III, or B cystinurea
-SLC7A9 gene -urinary excretion: moderate increase in cystine and dibasic amino acids -intestinal absorption is nearly normal to severely impaired
example of a frameshift mutation
-Tay-Sachs
what is a cherry spot behind the retina indicative of?
-Tay-Sachs
stop codons
-UAA -UAG -UGA
termination codons
-UAG -UAA -UGA
mutation prediction models
-Wijnen -PREMM -MMPro -Bethesda Criteria (2003) -Amsterdam Criteria (1999)
what are keyscher-fleischer rings indicative of?
-Wilsons disease
inheritance of Menkes syndrome
-X- linked recessive
inheritance of hemophilia A
-X-linked -more common in males -females can exhibit symptoms depending on X inactivation
inheritance of G6PD deficiency
-X-linked recessive -most prevalent anemic condition in the world
triple X syndrome
-XXX
symptoms of Kleinfelter's syndrome
-XXY -male -rounder abdomen like a woman, small testes, breast tissue -often infertile
where is the gene for factor IX located? hemophilia B
-Xp27
nonsense mutation
-a DNA base change can result in an amino acid being replaced by a stop codon -UGU to UGA (U to A mutation)
single nucleotide polymorphism (SNP)
-a DNA sequence variation occurring when a single nucleotide in the genome differs between members of a species or paired chromosomes in an individual
frameshift mutation
-a base or bases are inserted or deleted from DNA in groups that are a factor of three -nucleotide gets inserted into the sequence and pushes the groupings that make each codon down -also occurs if one nucleotide comes out and the others shift the other way
frameshift mutation
-a base or bases are inserted or deleted from DNA in groups that are not a factor of 3 -Normal RBC: GTC CAC CTC ACA CCC GAA GAA -Frameshift due to insertion: GTC CAA CCT CAC ACC CGA AGA
monosomic cell
-a cell lacking one chromosome of a diploid complement
evolution
-a change in the genetically inherited frequencies of alleles over time
what determines the DNA sequence
-a combination of genetic controls and epigenetic mechanisms -promoters, enhancers and silencers, RNA splicing and editing
what does the co-occurence of MENII and Hirschsprung disease in some families with the same mutations suggest?
-a common mechanism for both disorders
mosaicism
-a condition in which two or more different karyotypes are consistently present in one individual (from different cells) -the degree of phenotypic expression of either karyotype depends on the percentage of cells within a given tissue that have a normal vs abnormal karyotype -varies by tissue and has its start early in embryonic life -represents an error in chromosome segregation after conception, which means that only some cells have the error and others do not
single nucleotide polymorphism (SNP)
-a difference in a single DNA building block, called a nucleotide -ex- may replace the nucleotide cytosine (C) with thymine (T) in a certain stretch of DNA
congenital adrenal hyperplasias
-a group of autosomal recessive disorders characterized by impaired cortisol synthesis -can be life threatening
how does the huntington gene display anticipation?
-a larger expansion is associated with an earlier onset of the disease and more severe symptoms -signs and symptoms tend to become more severe and appear earlier as the disorder is passed from one generation to the next
DNA in mammals
-a linear, double-stranded structure composed of multiple units of four different nitrogenous bases each attached to a sugar molecule -the bases in each strand are connected by phosphate groups -the two individual strands are held together loosely by hydrogen bonds interacting between the base pairs of the strands
genetic testing for cystic fibrosis
-a panel is recommended for the most common 25 mutations -a negative report for one or both members of a couple does not exclude the possibility of an affected offspring -dependent on other factors such as racial or ethnic background of each parent, the specific mutations being tested, and whether both parents are tested
example of mosaicism
-a person with trisomy 21 may have some blood and skin cells showing a 47,XY+21 karyotype and some blood and skin cells showing a 46,XY karyotype -can have classic trisomy 21 features but normal to high intellectual functioning -the explanation of the unaffected intellectual function is mosaicism in brain neurons with a high percentage of normal neurons compared to trisomy 21 neurons
phenotype
-a person's expressed physical traits
testing for micro deletion or micro duplication syndromes- description of disorders, examples and types of tests
-a piece of a chromosome is missing or duplicated, too small to be seen on a standard karyotype -DiGeorge (VCF) Syndrome (22q11); Williams syndrome (del 7q11) -FISH
micro deletion or micro duplication syndromes and examples
-a piece of a chromosome is missing or duplicated, too small to be seen on a standard karyotype -DiGeorge (VCF) syndrome, williams syndrome
transition- point mutation
-a purine is replaced by another purine, a pyrimidine is replaced by another pyrimidine -at the nucleotide level
gene amplification
-a small piece of chromosome is duplicated over and over -results in an increased expression of an oncogene
Apolipoprotein E (APOE)
-a susceptibility gene (not casual) located on chromosome 19q13.2 -predisposes to late onset alzheimers -critical role in triglyceride rich lipoprotein metabolism and cholesterol homeostasis -originally known risk factor for CV disease -also used to determine if someone has demential or alzheimers
polymorphism
-a variant allele that has a frequency of at least 1% in the population GGC ACG TTG CCA- 70% GGC TCG TTG CCA- 30%
promoter region
-a very short sequence that clusters within a few hundred nucleotides from the transcription start site -important in establishing which segments of a DNA strand will be transcribed -major factor- on-off switches in genes
genetics of Romano-Ward syndrome- LQT
-accounts for most LQT syndrome cases -nearly 30% of cases do not have mutations in one of the 5 genes -additional genetic loci, representing genetic heterogeneity of the syndrome, appear to be involved in the etiology
methylation tags- histones
-activate or repress genes
4 nucleotide bases in DNA
-adenine -thymine -guanine -cytosine
complimentary base pairs-DNA
-adenine and thymine -guanine and cytosine
what is galactosemia and what does it lead to?
-affected infants are unable to utilize galactose found in milk -leads to liver enlargement, malnutrition, ID, and cataracts
risk factors for prostate cancer
-age -positive family history -diet- increased risk with high sat fat intake -nationality/race -exposure to heavy metals -lifestyle- physical activity and weight management reduce risk -smoking
hemophilia B
-aka Christmas disease -reduction of factor IX -much smaller gene located on Xp27
what is hereditary nonpolyposis colorectal cancer (HNPCC) also known as? what is the prevalence? what percentage of colorectal cancers are HNPCC? is it dominant or recessive?
-aka Lynch syndrome -1/200 to 1/800 -5% -autosomal dominant
genome
-all DNA, chromosomal and mitochondrial, coding and non-coding regions
what do all cancers have in common?
-all are genetic in origin
who should family history of cardiovascular disease be obtained in?
-all asymptomatic adults
epigenetics
-all phenomena that without affecting the DNA sequence can produce heritable changes in how genomes function -different biochemical mechanisms that occur in our body that dictate whether a gene gets expressed or not -can cause diseases in some cases -can be stably transmitted from one cell generation to the next in the form of cell memory -can be reversible -literally means above or on top of genetics
epigenetics
-all phenomena that without affecting the DNA sequence, can produce heritable changes in how genomes function -literally means above or on top of genetics -the study of stable, heritable changes in gene function that are not due to changes in the primary sequence of DNA -DNA methylation, histone modification, and non-coding RNAs (ex- microRNAs) -cells can exhibit different phenotypes and possess the same genotype
if there is a couple where the father has an x-linked dominant trait for a disease and the mother is unaffected, what are the chances that the sons or daughters of the couple will be affected?
-all sons of affected male and normal female are normal -all daughters of affected male and normal female are affected
what happens if nondisjunction occurs in a primary spermatocyte during meiosis 1?
-all the sperm derived form the primary spermatocyte will be abnormal and all zygotes will have an aberrant chromosome complement
what happens to the chromatids if nondisjunction occurs during meiosis 1?
-all three chromatids in a fertilized egg have unique parents (or really grandparental) origin
mutation
-allele frequencies change in response to mutation -can introduce new alleles -can convert one allele to another -mutation has a minor impact (most are silent unless coupled with another effect such as small population size or selection)
gene flow
-alleles can move between populations when individuals migrate and mate -underlies evolution
allele variation/allelic heterogeneity
-alleles differ in their expression because they are defined by different mutations and this result in different versions of the same protein -can cause people with same disorder to experience variable severity of symptoms
what does the disease severity of congenital adrenal hyperplasias correlate with?
-allelic variations -more than 100 CYP21A2 mutations are known- duplications, deletions, and rearrangements
purpose of mRNA
-allows the message to reach the ribosome while the gene itself remains in the nucleus to be used as a template for more mRNA when appropriate
hunters disease- lysosomal storage disease
-almost exclusively in males -GAGs build up in lysosomes because of lack of enzyme -medical problems occur as buildup occurs -by 2-4, symptoms begin to emerge -initial signs and symptoms can suggest other problems leading to delayed diagnosis
disorders caused by problem in type 4 collagen
-alport syndrome
what do tumors arise from
-alterations in the cell cycle
what type of disease is CML?
-always genetic -translocation of chromosome causes it
complex diseases of the brain
-alzheimers -parkinsons -schizophrenia
phenylalaline
-amino acid that is the starting point for a series of reactions essential in metabolism
diagnostic tests for down syndrome
-amniocentesis -chronic villas sampling (CVS) -percutaneous umbilical blood sampling (PUBS)
enhancers
-amplify transcription
amyloid plaques- alzheimers
-amyloid is a general term for protein fragments that the body normally produces -beta amyloid snipped from APP and is usually broken down and eliminated -in alzheimers, fragments accumulate to form hard, insoluble plaques
symptoms of Alzheimers
-amyloid plaques, tangles -often seen in autopsies
what is G6PD?
-an enzyme active in all types of cells and involved in carbohydrate metabolism -converts glucose to ribose-5 phosphate, an essential component of nucleotides -this conversion produces a molecule called NADPH, which plays a role in protecting cells (RBCs) from reactive oxygen species
why does a population bottleneck enhance the effects of a genetic drift?
-an event severely reduces the number of individuals in a population -only those who survive can reproduce -only their traits will be passed on -new population loses some genetic diversity
what does a defective CFTR protein in cystic fibrosis lead to?
-an impaired ability to secrete chloride ions -leads to failure of chloride to cross cell membranes, caused a compensatory influx of sodium ions along with water, leading to dehydration at the cellular surface and causing the sticky mucus characteristic
what can natural selection result in?
-an increase in the frequency of an allele- positive selection -a decrease in the frequency of an allele- negative selection
Diseases that result from genomic imprinting
-angelman syndrome -Prader Willi syndrome
signs and symptoms of Fabry disease- lysosomal storage disease
-angiokeratomas and acroparathesia -pain from minutes to days -pain related to deposition of sphingolipids in small vessels -can occur during stress, exercise, fatigue
examples of genomic imprinting
-angleman's -prader-willi's
major classes of drugs that can cause long QT syndrome
-antiarrythmic drugs -certain non sedating antihistamines (terfenadine and astemizole were removed from the market) -macrolide antibiotics -antipsychotics -antidepressants
what can cause hemolytic anemia in people with G6PD Deficiency?
-antimalarials -aspirin -probenecid -vitamin k -fava beans (favism)
what should G6PD deficiency be considered as the cause of?
-any chronic nonspherocytic hemolytic anemia across all populations -newborn screening done in countries with high prevalence
agonist
-any drug that binds to a cell's receptor site and causes the same response as the naturally occurring hormone or substance
population
-any group of members of the same species in a given geographical area potentially capable of mating and producing fertile offspring
specific indications for fragile X syndrome testing
-any male or female with intellectual impairment, autism, other behavioral disorders -positive family history of infertility, early or premature menopause, intention tremor, ataxia, memory or cognitive decline deficits, Fragile X syndrome, other
genetic testing
-any test, the result of which would prompt the health professional to alert the family members of potential risk -can involve the analysis of human DNA, RNA, chromosomes, proteins, or metabolites -genogram/pedigree can also be a type of genetic testing
autosomal
-anything from chromosome 1 to chromosome 22 -not sex chromosomes
what is considered a full mutation in fragile X?
-anything over 200 repeats
where can mutations occur in DNA?
-anywhere
complementary bases
-are in two opposite strands of DNA -complementary DNA strands must remain perfectly parallel to each other
what do you need to ask about when collecting information on cardiac diseases and age of onset when collecting a family history?
-ask about specific diseases and symptoms: stroke, MI, arrhythmias, cardiomyopathies, congenital heart defects, syncope, chest pain -ask about procedures such as "bypass", angioplasty, stents, ICDs, PPMs -ask about cardiac screening: ECHO, ECG, Caths
how many generations have to be listed in a pedigree?
-at least 3
where is warfarin's action directed?
-at the enzyme Vitamin K epoxide reductase complex 1 (VKORC1)
examples of multifactorial-polygenic inheritance
-atopic conditions -diabetes -cancer -neural tube defects -pyloric stenosis -cleft lip -cleft palate -congenital hip dysplasia -club foot
examples of multifactorial-polygenic diseases
-atopic conditions, diabetes, cancer, NTDs, pyloric stenosis, cleft lip, cleft palate, congenital hip dysplasia, club foot
2nd degree relation
-aunts/uncles -nieces/nephews -grandparents -grandchildren -half-siblings
fluorometric assay test
-automated test that produces fewer false positives than Guthrie test
inheritance of familial hypercholesterolemia
-autosomal dominant
inheritance of romano ward syndrome
-autosomal dominant
mendelian inheritance
-autosomal dominant -autosomal recessive -x-linked dominant -x-linked recessive
is hunting tons disease dominant or recessive? penetrance?
-autosomal dominant -complete penetrance
is achondroplasia dominant or recessive? what is the penetrance?
-autosomal dominant -complete penetrance -20% have a parent with achondroplasia
inheritance of vWD
-autosomal dominant -males and females are affected equally -often seen in every generation- 50% chance of offspring being affected
genetics of types II, III, and IV OI
-autosomal dominant -missense mutation that alters the glycine codon
is neurofibromatosis 2 dominant or recessive? when is the onset seen? penetrance?
-autosomal dominant -onset late teens -complete penetrance by age 60
inheritance of OI
-autosomal dominant -sometimes spontaneous mutation
is neurofibromatosis 1 dominant or recessive? how is it expressed? penetrance?
-autosomal dominant -variable expression -complete penetrance before age 5
von Willebrand's disease
-autosomal dominant transmission -missense mutations or large deletions alter the amount of von willebrand protein that normally promotes platelet adhesion; also a carrier of factor VIII in the clotting cascade
genetics of type 1 osteogenesis imperfecta
-autosomal dominant with variable expressivity -due to nonsense, frameshift, or splice site mutations in COL1A1 gene leading to decreased a1 chains
single gene disorders and examples
-autosomal dominant, recessive or x-linked -marfan, cystic fibrosis, sickle cell, duschene MD
testing for single gene disorders- description of disorders, examples, and types of tests
-autosomal dominant, recessive, or x-linked -Marfan, Cystic fibrosis, sickle cell, Duchene MD -DNA sequencing, mutation analysis, PCR
inheritance of cystinurea
-autosomal recessive
is PKU recessive or dominant? what is the incidence? who is it most common in?
-autosomal recessive -1 in 10,000 live births -most common in Euro-Americans from Ireland and Scotland
is maple sugar urine disease dominant or recessive? what is the incidence? who is it most common in?
-autosomal recessive -1:185,000 infants worldwide -old order mennonite population- 1:380
is galactosemia recessive or dominant? what is the incidence?
-autosomal recessive -classic galactosemia occurs in 1 in 30,000-60,000 -type II and III are less common- type II: 1 in 100,000 newborns and type III very rare
rare form of type III osteogenesis imperfecta
-autosomal recessive -related to consanguinity -most common form in africa
inheritance of sickle cell
-autosomal recessive -will have carriers
Gauncher disease- lysosomal storage disease
-autosomal recessive disease with mutation in glucocerebrosidase gene -causes accumulation in phagocytic cells, which causes distention and can displace bone marrow and demineralization, as well as hypoxia in lungs, etc
inheritance of Jervell and Lange-Nielsen syndrome- LQT
-autosomal recessive form -rare
inheritance of retinoblastoma
-autosomal- on chromosome 13 -have to have 2 mutated genes to get the cancer- you get one from each parent -one can be present in gremlin (in every somatic cell and passed onto subsequent generations) -the second mutation would be somatic and within retinal cell -predisposition is inherited in autosomal dominant fashion, but pathology at cellular level is recessive mechanism
preventing complications in sickle cell
-avoid triggers -transcranial doppler
how to prevent complications of SCD
-avoid triggers -use transcranial doppler (TCD)
examples of drugs metabolized by thiopurine methyltransferase
-azathioprine -mercaptopurine -thioguanine
examples of drugs metabolized by Thiopurine Methyltransferase (TPMT)
-azathioprine (AZA) -Mercaptopurine (6-MP) -Thioguanine (6-TG)
Guthrie test
-bacterial inhibition assay -least expensive screening method for determining excess phenylalanine in the blood, but other tests are used to confirm
checkpoints in the cell cycle
-balance cell division and cell death -each stage (G1, S, G2, and m) has an associated checkpoint
extensive drug metabolizer
-balanced -"steady state" -after MEC is first achieved, drug absorption is equal to drug elimination -patient tends to respond in the expected way to standard drug dosages
why did the co-administration of citalopram (celexa) and CYP3A4 inhibitor ketoconazole not significantly affect the pharmacokinetics of celexa?
-because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance -citalopram steady state levels were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of celexa, suggesting that coadministration with celexa of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on celexa metabolism
why is DNA replication needed with every mitosis?
-because each new cell created must have a complete genome
how can you predict the sequence of one DNA strand if you know the sequence of the other?
-because of complementary base pairs
why is MSUD one of the earliest detected inborn errors?
-because of the maple sugar odor in urine -newborn screen detects high levels of leucine and infants quickly demonstrate FTT
why is G6PD Deficiency seen more in males?
-because of x-linked recessive inheritance
codeine in ultra-rapid metabolizers
-become more intoxicated with low doses of codeine
codeine and ultrafast metabolizers
-become more rapidly intoxicated with low doses of codeine
classic albinism
-best-described condition affecting pigment production -results from lack of tyrosinase -individuals with PKU can have this- high phenylalanine means low tyrosine
drugs metabolized by CYP2D6
-beta blockers -antiarrhythmics -antidepressants -narcotics
when do huntingtons symptoms show up?
-between 30-40 years
types of congenital heart disease- complex cardiac diseases
-bicuspid aortic valve -ventricular septal defect -atrial septal defect -patent ductus arteriosus -tetrology of Fallot -hypoplastic left heart syndrome
defect in Wilson disease
-biliary excretion of copper
symptoms of vWD
-bleeding is more common in mucous membranes or after routine operations -less severe bleeding than other types of hemophilia
do heterozygous or homozygous individuals with familial hypercholesterolemia manifest symptoms?
-both
implications of schizophrenia
-both genes and environment play a role and affect neurologic development -schizo- brains are generally smaller and cerebral ventricles are bigger
major sites affected by lysosomal storage diseases
-brain -skeleton -heart -liver -spleen
disruption
-breakdown of normal tissue
what are people who are carriers of the ATM missense mutation at a heightened risk for
-breast cancer
symptoms of Menkes syndrome
-brittle, tangled, sparse, steely, or kinky hair -lack of hair color -pudgy cheeks and abnormal eyebrows -often born pre-mature -hypothermia -hyperbilirubinemia (can appear jaundice) -severe developmental delays -seizures, dementia -subdural hematoma bc of weakened arteries -osteoporosis
how are normal copper levels achieved in the liver?
-by a rate-limiting step in the production of ceruloplasmin -excretion into the bile
how is lysosomal storage disease severity characterized?
-by age of onset -clinical course -whether CNS is involved
drugs metabolized by CYP3A
-calcium channel blockers -benzos -statins -acetaminophen
what is the rate of spontaneous mutations leading to DMD or BMD?
-can be as high as 35%
is down syndrome caused by a numerical or structural chromosomal error?
-can be caused by either
heterozygous females- DMD
-can have muscle weakness, fatiguability, and mild respiratory and cardiac problems
inherited cancers
-can identify pattern of inheritance -often autosomal dominant -occur often at much younger age- under 50
familial cancer
-cancers that occur in higher than expected frequency in families -cannot identify the pattern of inheritance with pedigree
what can CGH testing not do? what does it cost?
-cannot detect changes at the gene level or mosaicism, so specific tests for FXS or Rett may be added -cannot detect balanced rearrangements (inversions or translocations) -$1800
the abnormalities or dysfunctions of neural crest cells- hirschprung
-carcinoid tumors -neuroblastoma -neurofibromatosis -pheochromocytoma -Hirschprung
clinical presentation of congenital adrenal hyperplasias
-cardinal feature- genital ambiguity -if not recognized and treated, both males and females undergo rapid postnatal growth and sexual precocity -severe enzyme deficiency leads to neonatal slat loss and death about 75% of classic cases have aldosterone deficiency with salt wasting, FTT, and potentially fatal hypovolemia and shock
classes of genes involved in cancer
-caretaker genes -oncogenes -tumor suppressor genes
male or female, male or female with trait, carrier- pedigree
-carrier can also be circle or square with dark circle in middle
what type of genetic test provides information about an asymptomatic person's risk for having a child with a specific autosomal recessive disorder in the future?
-carrier test
induced mutations
-caused by environmental agents that enter the cell -underlying cause originates outside the cell -mutagen- a chemical or physical agent that can induce a DNA mutation
genetics of duchene muscular dystrophy (DMD) and Becker MD
-caused by mutations in the dystrophin gene -located Xp21: largest known gene contains >70 exons and is 0.001% of entire genome -DMD and BMD caused by mutations in same gene locus -deletions: 65% DMD; 85% BMD -duplications, point mutations, small insertions, or deletions: 30% DMD -spontaneous mutations can be as high as 35%
Dechene and Beckers Muscular Dystrophy
-caused by mutations in the dystrophin gene -located Xp21; largest known gene- contains >70 eons and is 0.001% of entire genome -dystrophin is found in skeletal, smooth, and cardiac muscle, and brain -caused by mutations in the same gene locus
antagonist
-causes the opposite reaction of an agonist -inhibits the expected cell function by preventing receptor interaction with agonist substances
somatic mutation
-cells of body affected -mutations can occur early or late stages of development -portion of body maintains mutation -acquired mutation after conception -can involve faulty DNA repair mechanisms -can happen before birth- not inherited from parents
RNA editing-less understood
-certain nucleotides will undergo deamination (removal of an amine group) or transamination (transference of an amine group), which changes the coding sequence of the mRNA -significance is unclear
point mutations
-changes occur in one or a few nucleotide base pairs -Ex- RAS gene converts a regulated proto-oncogene to an unregulated oncogene, accelerating growth
example of population bottleneck
-cheetahs are difficult to breed in zoos because sperm quality is poor and many newborns die -results in lack of genetic diversity
disorders caused by problem in type 2 collagen
-chondrodysplasias
prophase- mitosis
-chromatin condenses into chromosomes -nuclear envelope disappears
telophase- mitosis
-chromatin expands -cytoplasm divides
what may hirschprung disease be associated with? is this common?
-chromosomal abnormalities or various genetic syndromes -70% of the cases occur as isolated disease, so no
what is renal genesis associated with?
-chromosomal anomalies: trisomy 21, trisomy 22, trisomy 7, trisomy 10, and Turner and Klinefelter syndromes -microdeletions of chromosome 22q11 and chromosome 11p13 (Wilms tumor)
most common mutations
-chromosomal mutations
mutation of caretaker gene
-chromosome instability and increased rate of mutation
metaphase- mitosis
-chromosomes align at the equatorial plate
deceased- pedigree
-circle or square with line through it
stillbirth- pedigree
-circle or square with line through it and letters "SB" under
where can enhancers and silencers be located?
-close or far away from the target gene
interpretation of red flags for common cardiac disease- higher risk
-closer relation -younger age of onset -more relatives
earliest symptoms of duchene muscular dystrophy
-clumsiness in walking with a tendency to fall -pseudohypertrophy of the calf muscles -positive Gowers sign -elevated creatinine kinase
example of drug activation by CYP450 enzymes
-codeine is a weak narcotic that exerts most analgesic effect on conversion to morphine, which is carried out by CYP2D6
codeine and someone with CYP2D6 deficiency
-codeine is not converted to morphine -person does not receive any pain relief -person has pain relief is they receive morphine instead of codeine
codeine in a person who has a CYP2D6 deficiency
-codeine is not converted to morphine and the person does not have any pain relief from the drug -pain is relieved if the person received morphine
exons
-coding portions of RNA
Preserving Employee Wellness Programs Act- 2015
-collection of information about the manifested disease or disorder of a family member shall not be considered an unlawful acquisition of genetic information with respect to another family member participating in workplace wellness programs or programs of health promotion or disease prevention offered by an employer or in conjunction with an employer-sponsored health plan -died at end of the congressional session- January 2017
long QT syndrome
-collection of related cardiac ion channel defects that alter myocardial depolarization, culminating in prolonged ECG QT intervals and a form of V tach called torsades de pointes (TdP)- hard to get someone out of this
long QT syndrome
-collection of related cardiac ion channel defects that alter myocardial depolarization, culminating in prolonged ECG QT intervals and a form of ventricular tachycardia (torsades de pointes- TdP) -the ion channel abnormalities predispose a person to arrhythmia that may result in sudden syncope or to a sudden drop in bp resulting in temporary loss of consciousness- can be solitary and rare or progress to sudden death
osteogenesis imperfecta (OI)
-collection of type 1 collagen disorders -due to mutation in COL1A1 or COL1A2 -7 subtypes
osteogenesis imperfecta
-collection of type 1 collagen disorders -due to mutation in COL1A1 or COL1A2 -seven subtypes recognized; types I-IV more common
steps when collecting family history
-collection- build rapport -interpretation- inform diagnosis, risk assessment -intervention- disease management
Bethesda Guidelines for testing colorectal tumors for microsatellite instability (MSI)
-colorectal cancer diagnosed under age 50 -presence of synchronous, metachronous colorectal, or other HNPCC-associated tumors, regardless of age -colorectal cancer with MSI-H histology diagnosed in a patient under 60 -colorectal cancer diagnosed with one or more first degree relatives with an HNPCC-related tumor, with one of the cancers being diagnosed under age 50 -colorectal cancer diagnosed in two or more first or second degree relatives with HNPCC-related tumor, regardless of age
multifactorial mutations and examples
-combination of genetics and environment -cleft lip and palate, club foot, NTDs
testing for multifactorial disorders- description of disorders, examples, and types of tests
-combination of genetics and environment -cleft lip and palate; club foot; NTDs -no testing
inherited disease
-comes down through mother and father
genetic disease
-comes down through replication of genes and chromosomes
ultimate diagnosis of down syndrome
-comes from analysis of the chromosome complement -individuals with down syndrome have 47 chromosomes rather than 46
germline
-coming from the egg or sperm cells
penetrance of DMD
-complete
sphingolipidoses- lysosomal storage disorders
-complex lipids and major component of cell membranes
family history: intervention- mendelian cardiac diseases
-confirm the diagnosis and degree of relation to affected individual -first degree relatives should be screened -genetic testing should begin in most severely affected person when possible
main symptom of Jervell and lange-nielsen syndrome- long QT
-congenital bilateral sensorineural hearing loss
most distinctive manifestations of Jervell and Lange-Nielsen syndrome- LQT
-congenital bilateral sensorineural hearing loss
hirschsprung
-congenital disorder characterized by the absence of neural crest-derided neurons along part of the distal large intestine
mitochondrial DNA
-contains 37 genes, all of which are essential for normal mitochondrial function -13 of these provide instructions for making enzymes involved in oxidative phosphorylation- process that uses oxygen and simple sugars to make ATP -remaining genes provide instructions for making transfer RNA (tRNA) and ribosomal RNA (rRNA)- these types of RNA help assemble protein building blocks (amino acids) into functioning proteins
3 classes of tumor suppressor genes
-control cell division -DNA repair -apoptosis or cell destruction
treatment for Wilson disease
-copper chelation
types of complex cardiac diseases
-coronary artery disease -hypertension -stroke -myocardial infarction -heart failure -angina pectoris
what clinical features does accumulation of glycosaminoglycans (GAGs) lead to? mucopolysaccharidoses- lysosomal storage diseases
-course facies, thick skin, corneal clouding and organomegaly, ID, growth deficiencies, skeletal dysplasias -all are autosomal recessive except Hunter syndrome, which is x-linked recessive
3rd degree relation
-cousins -great aunt, great grandparent, etc
IVF
-cryo preserved eggs and sperm/ frozen embryos
where is the GALE gene located?
-cytogenic- 1p36-p35 -molecular location on chromosome 1- base pairs 23,795,598 to 23,800,803
where is the GALT gene located?
-cytogenic- 9p13 -molecular location on chromosome 9- base pairs 14,646,588 to 34,650,597
lysosomes
-cytoplasmic organelles that enzymatically degrade glycoproteins, glycolipids, mucopolysaccharides
treatment for Menkes syndrome
-daily copper histidine injections
international summit on human gene editing
-december 2015- moratorium on using CRISPR on gremlin cells until all safety issues and societal concerns were addressed -February-July 2016- examined issues of patient advocacy, public engagement, international governance, applications, race, morality and religion in public policy
lab findings in Menkes syndrome
-decreased serum copper 0decreased liver copper -increased intestinal copper -decreased ceruloplasmin
lab findings for Menkes syndrome
-decreased serum copper levels -decreased liver copper levels -increased intestinal copper levels -decreased ceruloplasmin
lab findings for Wilsons disease
-decreased serum copper levels -increased liver copper levels -increased urinary copper levels -decreased ceruloplasmin
lab findings in Wilson disease
-decreased serum copper levels -increased liver copper levels -increased urinary copper levels -decreased ceruloplasmin
what does decreased ceruloplasmin cause- copper
-decreases copper carrying capability -decreased iron binding to transferrin (plays a role in releasing iron from cells) -decrease of other copper-dependent enzyme reactions
pre-implantation genetic testing
-decreases risk of passing on inherited conditions -exact mutation must be known -may be used when member of family needs bone marrow donor -multiple eggs are retrieved, fertilized, and grown in culture -day 3- embryo biopsied, 1-2 cells removed w/ no harm to embryo -PCR or FISH done -unaffected cells transferred to woman's uterus -not typically done for interfile couples
cystic fibrosis
-defective CFTR proteins result in an impaired ability to secrete chloride ions -leads to a failure of chloride to cross cell membranes and a compensatory influx of sodium ions in water, leading to dehydrations at the cellular surface and the sticky mucus disease characteristic
defect that causes PKU
-defective PAH enzyme -this normally breaks down phenylalanine
lysosomal storage disorders
-deficiencies in the enzymes responsible for the degradation of the substrates in lysosomes result in their accumulation -clinical symptoms are variable but all are progressive
Tay Sachs- lysosomal storage disease
-deficiency of lysosomal enzyme hexosaminidase A, resulting in accumulation of gangliosides -autosomal recessive -mutation in the A subunit
phenylketonuria
-deficiency of phenylalanine hydroxylase -infant has high concentration of phenylalanine in the blood as a result -high concentration leads to increased rate of formation of phenylpyruvic acid, which is excreted in the urine -phenylpyruvic acid inhibits pyruvate dehydrogenase complex, which is important in glucose metabolism and synthesis of fatty acids in individuals -individual will have lack of myelin formation, decreased brain size, and mental retardation
Hemophilia A
-deficiency or absence of clotting factor VIII results in impaired thrombin production -gene for Factor VIII is large and located on tip of Xq28
hemophilia A
-deficiency or absence of clotting factor VIII results in impaired thrombin production -caused by base pair changes, deletions, frameshift mutations, and protein truncating mutations
what mutation causes severe cystic fibrosis symptoms?
-deletion of 3 base pairs coding for phenylalanine -severe presentation when both alleles have deltion
deletion of 15q13.3
-deletion of one copy of this region- inherited in 75% of the cases- can cause a syndrome characterized by seizures, schizophrenia, and autism -this deletion is also found in unaffected individuals, however
risk for schizophrenia
-demonstrates a strong genetic component -risk increases among close relatives -1% of general population
pharmacogenomic genetic testing
-determines how an individual is likely to respond to a range of drugs -helps to tailor the most effective drug and dose
why is a person often not diagnosed with fragile X tremor ataxia syndrome?
-diagnosis is often missed because symptoms can be attributed to increasing age
purposes of genetic testing
-diagnostic -predictive -carrier -prenatal -preimplantation -newborn screening -pharmacogenomic
current pregnancy- pedigree
-diamond- unknown sex -circle or square- girl or boy -all have "P" in them
genetic regulation- genes
-dictates the form of the cell, how it behaves, and its identity
treatment of familial hypercholesterolemia
-dietary management -medications- statins -novel gene therapies
correlation between the number and activity of functioning LDL receptors in familial hypercholesterolemia
-direct -heterozygotes have half the number of normal LDL receptors -homozygous individuals have no or exceedingly few receptors
pleiotropic disorders
-disorders that have multiple phenotypic effects from a single event -can result in several clinical presentations
significance of Hardy-Weinberg equilibrium
-disproved the assumption that dominant traits increase while recessive traits decrease
interpretation of red flags for common cardiac disease- lower risk
-distant relatives -older age of onset -fewer number of relatives
intronic mutations
-do not change the protein product -may be associated with disease
multifactorial- polygenic inheritance
-does not follow Mendelian inheritance pattern -involves both genetic and environmental factors -means multiple genes are involved in the disease
multifactorial inheritance- polygenic
-does not follow mendelian inheritance pattern -involves both genetic and environmental factors
diagnostic genetic testing
-done to confirm or rule out a known or suspected genetic disorder in a symptomatic individual
is DNA single or double stranded
-double
nucleosome
-double helix twist of DNA around the octamer of the histone
what does it mean if you have a parental history of heart attack <50
-doubles risk of heart attack in men -increases risk in women by 70%
example of a genetic disease
-down syndrome -chromosomal abnormality
what are cytochrome P450 enzymes important in?
-drug detoxification -drug activation
what causes hemophilia A
-due to base pair changes, deletions, frameshift mutations, and protein truncating mutations
what causes hemophilia B?
-due to hundreds of different missense, nonsense, frameshift, and deletion mutations
when can diagnosis of hemophilia A be made?
-during first year of life
where is the extra chromosome in down syndrome acquired?
-during the production of the egg by the mother -5%-15% of the time is from the father
symptoms of Duchene Muscular Dystrophy
-earliest- clumsiness in walking with a tendency to fall -pseudohypertrophy of calf muscles- muscle breaks down and is replaced with fat -positive Gowers sign- will walk up legs to stand or sit up from floor -elevated creatinine kinase from muscle breakdown -majority unable to walk by age 12
familial alzheimers disease (FAD)
-early onset that is clinically and neurologically indistinguishable from late onset -autosomal dominant over multiple generations
what is homozygous familial hypercholesterolemia associated with?
-early-onset coronary heart disease -death from MI before age 30 is common
other causes of long QT disorder
-eating disorders -stroke
clinical features associated with a renal anomaly
-edema -exstrophy of the bladder -anuria-oliguria -aniridia -supernumerary nipples -hypertension -recurrent UTIs -abdominal mass -oligohydramnios -imperforate anus -ambiguous genitalia -hemihypertrophy -preauricular pits and ear tags -polydipsia -prune-belly abdomen -polyuria
disorders caused by problem in type 3 collagen
-ehlers-danlos syndrome
disorders caused by problem in type 5 collagen
-ehlers-danlos syndrome
does retinoblastoma occur with or without a family history?
-either -40% germinal and can affect both eyes -60% non-germinal and usually affects one eye
when can meiotic nondisjunction occur?
-either during the first or second meiotic division
when can nondisjunction occur in meiosis?
-either in the first or second stage, meiosis I or meiosis II
permutation for fragile X syndrome
-either parent can have a permutation for fragile X -depending on the number of repeats in the permutation of the parent that is passed to the offspring, there is a chance that the permutation can develop into the full disease during embryonic development -the more repeats, the higher the chance
why should a physician be cautious about a positive Guthrie test? (PKU types I-III)
-elevated tyrosine associated with low birth weight, seen in infants on high-protein diets, and with vitamin C deficiency may also cause a positive result -liver disease and galactosemia can cause positive result
normal function of tumor suppressor genes
-encode proteins that inhibit proliferation and prevent or repair mutations
BRCA 1 gene mutation
-encodes 1863 AA polypeptide -40-50% of AD breast cancers -risk: 80% penetrance by age 70
BRCA 2 gene mutation
-encodes 3418 AA protein -100 different variants; 30% of families -risk- 50-85% in females and 6% in males -associated with prostate, pancreatic, and laryngeal cancers
what are people with hereditary nonpolyposis colorectal cancer (HNPCC) at increased risk for?
-endometrial cancer: lifetime risk is 80% -ovarian cancer, renal pelvis, brain, small bowel, hepatobiliary tract, skin cancer
DNA methylation
-enzymatic methylation of cytosine bases -limited to cytosines
G6PD
-enzyme active in all types of cells and involved in carbohydrate metabolism -converts glucose to ribose-5 phosphate, an essential component of nucleotides -this conversion produces a molecule called NADPH, which plays a role in protecting cells from reactive oxygen species
Thiopurine Methyltransferase (TPMT)
-enzyme used to metabolize drugs used to treat childhood leukemia, rheumatoid arthritis, or IBS
what is nondisjunction? when can it occur?
-error in the separation of chromosomes -may occur in the division of somatic cells (mitosis) or in the formation of gametes (meiosis)
what can cause non-random mating?
-ethnic or religious preferences -isolated communities -cultures in which consanguinity (marriage between relatives) is more prominent -events of history
what enhances the effect of genetic drift?
-events that create small populations
what enhances the effects of genetic drift
-events that create small populations -founding a new population, bottlenecks (natural disaster, famine), geographic separation, cultural separation
inheritance of MRD
-evidence of autosomal dominant but most are associated with chromosomal abnormalities
population genetics
-examines the ways in which allele frequencies change in human populations over time -a species with lots of different alleles will have more genetic diversity -the study of the genetics of a population and how the alleles vary or stay the same over time
thrombophilia
-excessive clotting -antithesis of coagulation disorders -increases risk for venous thrombosis- lower extremities and pulmonary emboli
environmental mutagens- risk factors
-exposure to harmful agents in food, air, and water
Trisomy X
-extra X chromosomes -47, XXX
Klinefelters Syndrome
-extra X chromosomes -47, XXY
tetrasomy X
-extra X chromosomes -48, XXXX
Pentasomy X
-extra X chromosomes -49, XXXXX
what are patients with familial adenomatous polyposis at an increased risk for?
-extracolonic tumors
difference between extrons and introns in DNA
-extrons are the parts of the gene that are used -introns are cut out
what does renal agenesis result from? what is absent?
-failure of the ureteric bud to develop between the 25th and 29th day of development -both ureters and renal arteries
societal concerns regarding genetics
-fairness in the use of genetic information -privacy and confidentiality -reproductive issues -clinical issues -uncertainties -conceptual and philosophical implications -health and environmental issues -commercialization of products
T or F: FXTAS affects more females than males
-false
T or F: in fragile X, the CGG expansion only occurs father to offspring
-false
example of an autosomal dominant condition showing incomplete penetrance
-familial breast cancer due to mutations in the BRCA1 gene -females with this have 80% lifetime risk, so penetrance is 80%
Li-Fraumeni Syndrome
-familial cancer disorder -autosomal dominant -higher risk for early onset cancer, predicting multiple affected family members commonly found in pedigrees -by age 30, 50% of individuals develop one of a variety of malignancies: soft-tissue sarcomas, osteosarcomas, brain tumors, breast or colon carcinomas, adrenal carcinomas, and leukemia
Li-Fraumeni Syndrome
-familial cancer disorder -high risk for early onset cancer, predicting multiple affected family members commonly found in pedigrees -by age 30, 50% of individuals develop one of a variety of malignancies: soft-tissue sarcomas, osteosarcomas, brain tumors, breast or colon carcinomas, adrenal carcinomas, and leukemia
what is one of the strongest influences on heart disease, stroke, diabetes, and cancer
-family history
20% of cases of prostate cancer may be considered familial if at least one of the following is true
-family history is positive for 3 or more first-degree relatives with the disease -3 or more generations exhibit the disease on the same side of the family -two or more close relatives have early-onset prostate cancer
risk factors for diabetes
-family history of diabetes -obesity -metabolic syndrome
red flags- family history
-family history of multiple affected family members with the same or related disorders, which may or may not follow an identifiable pattern in the family -earlier age at onset of disease than expected -condition in the less-often-affected sex -disease in the absence of known risk factors -ethnic predisposition to certain genetic disorders -close biological relationship between parents
no expansion- fragile X
-father to offspring
what does the poor perfusion and oxygenation resulting from sickle cell disease result in?
-fatigue -pain -organ damage- stroke, eye, gallstones, lungs, liver, kidneys -increased infections
what are common fears in families regarding clinical genetics
-fear of losing health insurance -fear of paying higher premiums -fear of losing employment
what fears can families have with regards to clinical genetics
-fear of losing health insurance -fear of paying higher premiums -fear of losing employment
how is fragile X inherited?
-female carrier has 50% chance- female carrier has premutation -male carriers only pass to daughters --if mom has premutation and she gets pregnant, the embryo can change from premutation to full mutation- does not matter if child is male or female -if dad has premutation, it will stay as a premutation- does not expand
why are X-linked recessive diseases usually only seen in males?
-females get 2 X's -most of the time, they will use the normal X -if body uses affected X, might have mild symptoms
how chromosomes are labeled
-first number is chromosome -p or q- p for petite or short arm, q for long arm -region -band -sub-band
chromosomal location of a gene
-first number is chromosome -then if long arm (q) or short arm (p) -then region number -then band number -then a decimal point, followed by the sub-band number -ex- 7q31.2
risk factors for multifactorial inheritance
-folic acid deficiency- 5X the risk -alcohol during pregnancy -teenage mothers -history of miscarriage -first born infants -mom with SB, diabetes, anticonvulsants
triplet repeats
-found in any region of the gene anatomy- promoter region, exon, intron -affects phenotype of offspring through unusual mode of inheritance -may result in loss of function, gain of function, RNA affects
in who is breast cancer most common?
-founders mutations in ashkenazi Jews, northern europeans, and icelandic populations
examples of events that create small populations and enhance the effect of a genetic drift
-founding a new population -bottlenecks (natural disaster, famine) -geographic separation (islands) -cultural separation
management of OI
-fracture prevention -PT and swimming -fracture management with casts, splints, wraps -braces to support legs, ankles, knees, wrists -use of canes, walkers, wheelchairs to reduce stress on weight-bearing bones -audiology evaluations -GI management -bisphosphonates synthetic -Bone marrow transplant -gene therapy
example of a triplet repeat
-fragile X syndrome
what is the most common cause of inherited mental impairment?
-fragile X syndrome
what is the most common identifiable cause of autism?
-fragile X syndrome
what is the most inheritable cause of intellectual disabilities?
-fragile X syndrome
example of an inherited disease
-fragile X syndrome -abnormality on the X chromosome where there is a certain gene area where a piece of the DNA is in triplicate
this associated fragile x disorder causes a spectrum of ovarian dysfunction
-fragile x primary ovarian insufficiency
what disorders are considered a fragile X associated disorder?
-fragile x syndrome -fragile tremor ataxia syndrome -fragile primary ovarian insufficiency
examples of mapping a trait geographically
-frequencies of galactokinase deficiency -C lines are gradients in allele frequencies between successive neighboring populations
incidence
-frequency in which a disease occurs in that population over a period of time -usually just new cases
what are uncommon manifestations that may occur with cystinurea?
-frequent UTIs -chronic backache -hematuria
what causes the pain in sickle cell?
-from sickle cells getting stuck in microvasculature -also causes organ damage
areas of the brain specifically implicated in schizophrenia
-frontal lobe -wernicke's area -occipital lobe -hippocampus -limbic system
robertsonian translocation
-fusion of two long arms of afrocentric chromosomes at the centromere, leading to the formation of 2 new chromosomes -most common chromosomal rearrangement -no problem if balanced
galactosemia
-galactose is an important component of cell membranes and brain lipids -ordinarily converted to glucose and oxidized to provide energy -when it is not transformed, it accumulates in various tissues, blood, and urine
treatment of galactosemia
-galactose-free diet -prompt treatment at birth -damage can occur in first few days -need family history for pre or peri-natal testing!
genetics of neurofibromatosis 1
-gene is Neurofibromin (NF1); 17q11.2 ->500 mutations described that disrupt expression -most gremlin mutations produce a truncated protein -certain mutations inactivate the tumor suppression function
where is the gene for factor VIII located? hemophilia A
-gene is large and located on tip of Xq28
fragile X tremor ataxia syndrome
-generally a permutation syndrome -neurodegenerative disorder affecting permutation carriers -late onset progressive cerebellar ataxia and tremor -becomes more evident as a person ages
what controls the number of receptors on cells?
-genes
how are collagen genes named
-genes are named started with COL, then numeral for type, then letter A, then second number denoting particular a chain
genomic imprinting
-genomic input of one parent's allele or alleles fails to contribute to the offspring's phenotype -occurs occasionally through the process of uniparental disomy (UPD), in which both chromosomes are contributed by only one parent
what does hydroxyurea do and why is it used in treatment of SCD?
-gives more fetal hemoglobin, which has a better oxygen capacity
Mild CAH
-glucocorticoid precursors accumulate and are converted to androgenic steroids, causing shortened stature, early puberty, severe acne, and civilization and infertility in females -mineralcorticoid synthesis can also be affected, resulting in electrolyte disturbances, hypotension, and syncope
G6PD
-glucose-6-phosphate dehydrogenase gene -2 normal alleles of G6PD located on Xq28 -B allele; B-, Mediterranean -A allele, A-, African -more than 140 mutations have been identified and divided int 5 classes of variants -almost all involve single amino acid substitution
aneuploid cells
-have an incomplete or unbalanced chromosome complement owing to a deficiency or excess of individual chromosomes
what do people with marfan syndrome usually die of?
-heart abnormality -sudden cardiac death from aortic aneurysm caused by rupture of the aorta because of weakness of he collagen -test for aortic aneurysm- echocardiogram
characteristics of deletion 22q.11 (DiGeorge/VCFS)
-heart defects -learning disabilities -psychiatric problems -speech/language deficits -dysmorphism
what holds the two strands of DNA together? why?
-held loosely together most of the time by weak hydrogen bonds -these weak bonds allow easy strand separation during the DNA replication phase of cell division
which bleeding disorders are x-linked recessive?
-hemophilia A -hemophilia B
maternal PKU
-high phenylalanine during pregnancy- toxic to development of fetus -mother may fail to inform physician that she has PKU or forgets about the special diet she had as a child -even if child does not carry the genetic mutation, the infant can be adversely affected
what is the spontaneous mutation rate of achondroplasia? how many mutations have been identified in FGFR3 gene?
-high- 80% -over 200
what partly regulates transcription of genetic material encoded in DNA?
-histone chemical modifications of histone proteins
treatment for fragile x primary ovarian insufficiency
-hormone therapies -reproductive options -also support groups
frequencies
-how often a particular gene variant occurs in a particular population -calculated for alleles, genotypes, and phenotypes
diagnosis of familial adenomatous polyposis (FAP)
-hundreds to thousands of adenomatous polyps at an early age -detectable at puberty or early adulthood by sigmoidoscopy or colonoscopy
example of triplet repeat disorder that is 100% penetrant
-huntington's
what are risk factors that increase cardiac risk that you should ask about when collecting a family history?
-hypertension -high cholesterol -tobacco -obesity -diabetes -sedentary lifestyle -alcohol abuse
types of mendelian cardiac diseases
-hypertrophic cardiomyopathy (HCM) -long QT syndrome (LQTS) -Brugada syndrome -dilated cardiomyopathy (DCM) -catecholanergic polymorphic ventricular tachycardia (CPVT) -arrythmogenic right ventricular cardiomyopathy (ARVC)
causes of sudden death in young athletes
-hypertrophic cardiomyopathy (HCM)- 36% -coronary artery anomalies- 17% -indeterminate LVH- possible HCM- 8% -myocarditis- 6% -ARVC- 4% -MVP- 4% -Tunneled LAD- 3% -CAD- 3% -AS- 3& -Ion channelopathies- 3% -other- 3% -normal heart- 3% -Dilated CM- 2% -Aortic rupture- 2% -other congenital HD- 2% -Sarcoidosis- 1%
electrolyte abnormalities that can cause long QT syndrome
-hypokalemia -hypomagnesia
newborn screening- genetic testing
-identifies individuals who have increased chance of genetic condition so treatment can be started
whole genome sequencing (WGS)
-identifies the order of individual bases in the DNA chin, rather than extra or missing regions of chromosomes -like CMA, WGS uses array technology to analyze many regions of the genome at once
morbid risk for schizophrenia
-if a person survives through the period of greatest manifestation (18-45) years, then will develop schizophrenia
transversion- point mutation
-if a purine replaces a pyrimidine or vice versa
angelman syndrome
-if both number 15 chromosomes are paternal with no maternal input
X-linked dominant inheritance- male affected
-if dad carries the X, he will have the condition -Dad will pass X to daughter, all daughters will end up with the disease -can never pass from father to son
what does 80% penetrance mean?
-if everyone has BRCA mutation, 80% will have breast cancer phenotype
X-linked dominant inheritance- female affected
-if female has one mutated X, can pass either affected or unaffected X to offspring- random -whoever gets mutation will have the disease
why would a point mutation matter?
-if it changes the protein that is created
why would a point mutation not matter?
-if the same protein or amino acid is still created- different nucleotide combinations can make the same protein
family history: intervention- complex cardiac diseases
-if using a clinical risk assessment tool, consider re-evaluating those who are at low/moderate risk using family history -adjust treatment and therapeutic goals -encourage communication of family history within the family
environmental factors associated with schizophrenia
-illegal drug use -winter and spring birth -pregnancy and delivery complications -delayed development -low IQ -immigration status -urban birth and domicile
what drug is used to treat chronic myeloid leukemia (CML)
-imatinib Mesylate (Gleevec)
cytochrome P450 Enzymes
-important in drug detoxification and activating drugs
APOE4- alzheimers
-important predictive risk factor for alzheimers, but 50% of people with AD don't have E4 allele
sapropterin (Kuvan)- drug therapy for PKU
-improves conversion of phenylalanine to tyrosine
type 1 collagen
-in bones, skin, tendons, ligaments, cornea, intervertebral disks, blood vessel walls
when should testing for G6PD deficiency be considered?
-in children and adults of mediterranean, african, or asian descent with an acute hemolytic reaction caused by infection, exposure to known oxidative drug, or ingestion of lava beans
when should diagnosis of G6PD deficiency be considered?
-in children with a family history of jaundice, anemia, splenomegaly, or cholelithiasis -especially those of mediterranean or african descent
where is the genome present?
-in every nucleus containing cell except mature sex cells
X inactivity
-in girls, who have 2 x chromosomes, the body randomly picks one X chromosome to inactivate because it only needs one -no proteins will be coded from inactivated chromosome -this is why it is more uncommon for girls to have x-linked recessive gene for a disease
how is RNA read?
-in groups of 3 called codons -start and stop codons
type 4 collagen
-in kidney, inner ear
telomerase in cancer cells
-in many cancer cells, telomerase activity is reactivated, allowing tumor cells to proliferate indefinitely -telomerase activity has been correlated with aggressiveness in several cancer, including prostate -potential new target for anticancer drugs
where are congenital adrenal hyperplasias more prevalent?
-in remote geographic areas such as Alaskan Yupiks
where is dystrophin found? DMD and BMD
-in skeletal, smooth, and cardiac muscle -brain
type 5 collagen
-in skin, ligaments, bones, tendons, muscles, extracellular matrix
type 3 collagen
-in skin, lungs, intestinal walls, blood vessel walls
what causes retinoblastoma
-inactivation of the RB1 gene: 13q14.3 -normally, this gene regulates the cell cycle at the G1 to S transition -RB gene product prevents transcription factors from enhancing cell division
aminoacidopathies
-inborn errors of amino acid metabolism that are generally the outcome of enzyme deficiencies that result in the accumulation of a substrate
what should be considered in all critically ill infants?
-inborn errors of metabolism
considerations for genetic testing
-incidence -benefit -treatment -cost -feasibility
penetrance of LQT syndrome
-incomplete
penetrance of Romano-Ward syndrome- LQT
-incomplete -30-50% of individuals harboring a disease-causing mutation in one of the 5 RW genes show no symptoms
penetrance of Jervell and Lange-Nielsen syndrome- LQT
-incomplete penetrance found in the heterozygous state -parents of a child with JLN syndrome are asymptomatic
penetrance of retinoblastoma
-incomplete since 90% of heterozygotes undergo the second somatic hit
penetrance of retinoblastoma
-incomplete since only 90% of heterozygotes undergo the second somatic hit
what does subbing history of heart disease mean?
-increase in odds of heart disease in men and women by 50%
what does binding of enhancers on DNA do?
-increases the rate of transcription -the factor binding to the enhancer may cause DNA to loop back onto the promoter region and interact with proteins binding in this region to increase initiation
other factors that increase the risk of developing a clot if you have factor V leiden
-increasing age -obesity -injury -smoking -surgery -pregnancy -hormone replacement therapy -OCP
migration
-individuals migrate and move genes from one area to another -genetic effects of migration are reflected in current populations -changes in allele frequency can be mapped across geographical or linguistic regions -allele frequency differences between current populations may be correlated to historical events or cultural differences
ATM- missense mutation
-individuals who receive two mutated copies of the ataxia telangiectasia mutated (ATM) gene have ataxia telangiectasia -carriers may be at an increased risk for breast cancer -the mutation changes a serine to a cysteine at amino acid 49 (Ser49Cys)
symptoms of MSUD
-infants quickly demonstrate FTT -neurologic symptoms begin 3-4 days after birth due to acidosis and hypogylcemia -flaccidity,hypertonicity, high pitched cry, opisthotonos posturing, cerebral edema -also milder forms with variability
X-chromosome inactivation
-inherit one X -chromosome from mother and one from father -once cells begin to differentiate, one X chromosome becomes inactive -remains permanently inactive -random (could be from mother or father) -remains in daughter cells -inactive X moves to the periphery of the cell nucleus- Barr body
predisposition of retinoblastoma
-inherited in an autosomal dominant fashion -pathology at the cellular level is a recessive mechanism
tangles- alzheimers
-insoluble fibers primarily of a protein tau which forms microtubules -in alzheimers, tau is abnormal and tubules collapse
tangles- alzheimers
-insoluble fibers primarily of a protein tau, which forms microtubules -in alzheimers, tau is abnormal and tubules collapse
genotype
-internally coded, inheritable information
what is the human genome project?
-international research effort to sequence and map all human genes -completed in 2003 -gave us genetic blueprint -revealed that there are probably about 20,000-25,000 human genes
defect in Menkes syndrome
-intestinal absorption of copper
what do you need to ask about when collecting information on the age and cause of death of family members when collecting a family history on a person who may have a complex cardiac disease?
-investigate drowning -single motor vehicle accident of unknown cause -other suspicious deaths- may mail presence of an inherited cardiac disease
translation
-involves the mRNA localizing to the ribosome and transfer RNA (tRNA) recognizing codons -the tRNA docks with the codon and brings along the appropriate amino acid -as translation progresses, the amino acids link together to form an amino acid chain
how is the polymerase chain reaction (PCR) helpful in the process of genetic testing?
-it increases the amount of DNA being tested, thus promoting accuracy
how does DNA fit inside the cell?
-it spools around proteins called histones
what type of genetic testing examines a person's chromosomes for variations in number or structure?
-karyotype
euploid karyotypes
-karyotypes of cells with normal chromosome complements -haploid (23 chromosomes) germ cells (gametes) and the diploid (46 chromosomes) somatic cells
testing for chromosomal mutations
-karyotyping -pcr
female nondisjunction
-klinefelters syndrome -triple- X
how is lactose processed in the body of someone with galactosemia?
-lactose is cleaved into glucose and galactose -there is no GALT, so the galactose 1-phosphate concentration rises to toxic levels, causing kidney failure, enlarged liver, cataracts, and brain damage
signs and symptoms of hemophilia A
-large bruises due to minor injuries -if severe form, may have 5 or more bleeds per month in joints, deep muscles- painful -mild disease- abnormal bleeding ice per year or 10 years
physical characteristics of fragile X syndrome
-large ears -long faces -broad forehead -high palate -elongated testicles -hyperextensible joints -hypotonia -indentation of chest -seizures -stabismus -mitral valve prolapse
oligohydramnios- renal agenesis
-leads to other deformations such as a constricted chest cavity, underdeveloped lungs, and pulmonary hypoplasia
oligohydramnios- renal agenesis
-leads to other deformations such as a constricted chest cavity, underdeveloped lungs, and pulmonary hypoplasia -causes deformation because of different pressures pushing on the fetus, which causes the symptoms -deformation sequence presents as Potter facies
what does a lack of G6PD do?
-leaves RBCs vulnerable to oxidant damage (hemolysis)
G6PD Deficiency
-leaves RBCs vulnerable to oxidant damage, causing hemolysis
Romano Ward caused by LQT3
-less than 5% of cases -mutation in SCN5A gene on chromosome 3 -codes for cardiac Na channel -sleep or undisturbed rest apparently triggers LQT3, suggesting that slowed heart rate is a risk factor
how long does it take to get results from PCR testing? what is required for it? how much does it cost?
-less than a day -requires less DNA but shorter stretches of DNA are analyzed -$300-500 -less expensive than southern blot
symptoms of retinoblastoma
-leukocoria- white pupil -strabismus- crossed eye- one eye- 25% is first noted bc of this
what is most responsible for drug metabolism?
-liver enzymes -especially cytochrome P450 (CYP450)
APP gene- alzheimers
-located on chromosome 21 -mutation increases beta-amyloid protein which forms amyloid plaques -rare cause of early onset FAD- only 10-15% of cases -clinical hallmarks: amyloid plaques and neurofibrillary tangles -also can occur in individuals with down syndrome by 3rd to 4th decade
familial adenomatous polyposis (FAP)
-loss of APC gene permits accumulation of B- catenin, a transcription factor, to accumulate in the nucleus and result in cellular proliferation -usually mutations are nonsense or frameshift
mechanisms of allele action
-loss of function -gain of function -protein alteration -dominant effects of recessive mutation
tumor suppressor genes
-loss of function of both copies needed for complete loss -in normal state, these genes put the brakes on cellular proliferation
triple screen- noninvasive screening test to determine if there is an increased risk for Down Syndrome
-low maternal serum a-fetoprotein -low unconjugated estriol -elevated human chorionic gonadotropin
does mRNA have introns and eons? mature RNA?
-mRNA has introns and exons -mature RNA- when introns are spliced out and only eons remain -ready for translation once mature
telomerase
-maintains the length and integrity of chromosomal ends, or telomeres -in normal cells, telomerase activity decreases with age and the number of cell divisions, yielding progressively shorter telomeres over time
drug absorption
-major site- small intestine -drugs go to the liver before entering the rest of the venous blood, the heart, and circulatory system
later symptoms of duchene muscular dystrophy
-majority unable to walk by 12 -disease progression leads to respiratory muscle weakness and cardiomyopathy -most die by age 20 -heterozygous females can have muscle weakness, fatiguability, and mild respiratory and cardiac problems
who is at an increased risk for fragile X tremor ataxia syndrome
-males and females in permutation range -around 40% for males over 50 -around 8% for females over 50
allelic variation of congenital adrenal hyperplasias
-many patients are compound heterozygotes for 2 or more mutant alleles, which causes a wide spectrum of phenotypes
what are all human autosomal trisomic conditions associated with?
-marked developmental disorders
where does mitochondrial DNA (mtDNA) come from?
-maternal gamete -females pass to both sons and daughters
unilateral agenesis
-may be asymptomatic and an incidental finding -adrenal gland is absent in <10% of cases -the ipsilateral fallopian tube in females and the seminal vesicle in males may be absent
symptoms of neurofibromatosis 1
-may develop hundreds of tumors that protrude through the skin -some may just have light brown skin spots (cafe-au-lait spots)
height of patients with mild CAH
-may have normal height compared with general population, but are short compared to their parents
APOE2- alzheimers
-may have protective effect by lowering risk and increasing age of onset -these findings are implications for genetic testing, drug treatment, and preventative drug compounds
hydroxyurea
-medication for sickle cell -increases the amount of fetal hemoglobin, which will not sickle- increases oxygen carrying capability -normally have fetal hemoglobin until age 3-4 months
treatment for fragile X tremor ataxia syndrome
-medications -OT -PT
symptoms of Tay Sachs- lysosomal storage disease
-mental and physical deterioration -blindness, deafness, atrophy, paralysis -cherry red spot on macula (mostly in french and jewish)
thiopurine methyltransferase (TPMT)
-metabolize drugs used to treat childhood leukemias, rheumatoid arthritis, or inflammatory bowel disease
methylation
-methyl group that attaches to cytosine and shuts off the gene -DNA is normal, but methylation shuts it off anyway -DNA methylation in our cells is limited to cytosines and occurs within the context of the dinucleotide CG (called CpG islands- p signifies the phosphate connecting C to G)
two examples of chemical tags that histones are equipped with
-methylation tags -acetylation tags
two examples of the chemical tags that histones are equipped with
-methylation- activate or repress genes -acetylation- tend to unwind DNA and activate genes
comparative genomic hybridization testing (CGH)
-microarray analysis, CMA -compares patient and control to hundreds of thousands of DNA segments on a grid (array) -reveals subtle duplications or deletions anywhere on chromosomes as small as 20 Kb -has 44,000 to 1 million probes on DNA chip-equivalent to a million simultaneous FISH tests
what can cause prader willi and angelman syndrome
-microdeletion (deletion of several genes) of chromosome 15 -uniparental disomy -imprinting error -no transcription occurs from a gene if an unmethylated allele is deleted and a methylated allele remains, or if both alleles are methylated
where is G6PD Deficiency common?
-middle east -africa -southeast asia
in what groups is G6PD deficiency common?
-middle east -africa -southeast asia -found in 10% of black males
neurofibromatosis- somatic mutation
-might only have some patchy areas on skin (cafe-au-lait spots)
Becker MD
-milder variant -later onset of skeletal muscle weakness and ability to walk by 30s -progress to death due to cardiomyopathy-related heart failure in mid to late adulthood
Becker muscular dystrophy
-milder variant than DMD- starts at adolescence -later onset of skeletal muscle weakness and the inability to walk by 30s -progress to death due to cardiomyopathy relayed to heart failure in mid to late adulthood
MEC
-minimum effective concentration
mutations that lead to an oncogene
-missense mutation (spontaneous or induced by a mutagen) -chromosome translocation -gene amplification -viral integration
von Willebrand disease
-missense mutations or large deletions alter the amount of vWF that normally promotes platelet adhesion
Retinoblastoma (Rb)
-model for tumor suppressor genes -most common intraocular tumor of early childhood -can be fatal if not treated
bleeding from vWD
-more common in mucous membranes or after routine operations
Duchene Muscular Dystrophy
-more severe -starts when child is younger- often walking or crawling
collagen
-most abundant protein found in body -family of extracellular proteins produced by fibroblasts -19 types -more than 1000 mutations have been described in collagen genes
point mutation
-most basic type of mutation that can occur in DNA -involves a change in one base, at one point along the DNA sequence -some mutations involve more than one base of DNA -not all mutations result in a change in a protein
point mutation
-most basic type of mutation that can occur in DNA -involves a change in one base, at one point along the DNA sequence -some mutations involve more than one base of DNA -not all point mutations result in a change in a protein
inheritance of renal agenesis
-most cases spontaneous -also evidence of autosomal dominant and recessive
do cells only have one receptor type? what does this mean?
-most cells have more than one receptor type -allows different drugs to affect the same cell in different ways
how many receptor types do most cells have?
-most cells have more than one receptor type -this allows different drugs to affect the same cell in different ways
osteogenesis imperfecta type IV
-most clinically variable -mild to severe -reduced stature, dentinogenesis imperfecta, adult onset hearing loss, variable degrees of osteopenia
what causes the most common form of congenital adrenal hyperplasias
-most common form (95%) caused by mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase enzyme which converts precursors of cortisol and aldosterone
what is achondroplasia? what is the incidence? what are the signs and symptoms?
-most common form of dwarfism -1:20,000 -macrocephaly with frontal bossing, mid face hypo-dasia, and genu varum
incidence of hirschprung
-most common form of functional intestinal obstruction in infants: 1:5000 live births -more common in males, with ratio of 4 to 1 -70% of the cases- Hirschsprung occurs as an isolated disease
nationality/race- risk factor for prostate cancer
-most common in north america and northwestern Europe -highest risk for blacks -70% more common in blacks than whites -lowest risk for asians
nationality- risk factors for breast cancer
-most common in white women -least common in Hispanic, asian, and black women
retinoblastoma
-most common intraocular tumor in early childhood- 1:20,000 -can be fatal if not treated
prostate cancer
-most common malignancy in men -second leading cause of death due to cancer in men -lifetime risk:10-14% -most cases are sporadic, 20% familial
type 1 Osteogenesis Imperfecta
-most common, milder form -skeletal osteopenia and fractures due to minor trauma -dentinogenesis imperfecta -joint hyper mobility -blue colored sclerae -hearing loss in 50% of adult patients
Romano Ward caused by LQT1
-most common; over 60% of cases -KCNQ1 gene on chromosome 11 -codes for potassium ion channel required for repolarization -triggered by exercise
breast cancer
-most commonly diagnosed malignancy of women in north america -15-20% associated with familial hisotry
role of nurse in pre-test counseling and consent
-most labs don't require a consent form -it is nurse's responsibility to counsel parents and document consent
gremlin Rb
-most severe type -tumor behind both eyes
expansion- fragile X
-mother to offspring
what gene causes Hirschsprung disease?
-multigenic -RET gene is of particular interest
risk factors for cancer
-multiple cancers in family -cancers occur at an earlier age <50 -2 or more primary cancers in a single individual -cases of cancer in unexpected gender
3 general steps involved in DNA repair
-mutated DNA is recognized and excised -the original DNA sequence is restored with DNA polymerase -the ends of the replaced DNA are ligated to the existing strand
oncogenes
-mutated version of proton-oncogenes- has change in expression of gene -at the cellular level, the oncogene is a dominantly acting gene and grows unchecked -results in gain of function
Wilsons Disease
-mutation in ATP7B gene prevents release of copper from hepatocyte -inability to use or excrete copper
LQT3 gene for Romano-Ward syndrome- LQT
-mutation in SCN5A gene on chromosome 3 -codes for cardiac Na channel -sleep or undisturbed rest apparently triggers LQT3, suggesting that slowed heart rate is a risk factor
what is Li-Fraumeni syndrome caused by? what is the inheritance?
-mutation in p53 -autosomal dominant
BRCA 1 and BRCA 2 in-frame mutations
-mutation in the BRCA1 and BRCA2 genes are known to greatly increase the lifetime risk of developing breast and ovarian cancer -some of the mutations in the BRCA2 gene are in-frame deletions -ex- the deletion of 15 bases resulting in the deletion of 5 amino acids from exon 18 of the BRCA2 gene was implicated in one family's susceptibility to breast and ovarian cancer
what causes Li-Fraumeni syndrome?
-mutation of p53 protein
LQT2 gene for Romano-Ward syndrome- LQT
-mutations in KCNH2 gene on chromosome 7 -codes for a potassium channel required for repolarization -provoked by auditory stimuli
what are 90% of cases of Jervell and Lange-Nielsen syndrome caused by? the other 10%? - LQT
-mutations in the KCNQ1 gene -KCNE2 involved in 10%
genetics of neurofibromatosis 2
-mutations in the Merlin gene; NF2; 22q12.2 -involved in membrane cytoskeletons
genetics of achondroplasia
-mutations in the fibroblast growth factor receptor 3 gene- FGFR3
hereditary nonpolyposis colorectal cancer (HNPCC)
-mutations in the repair enzymes decrease effective repair -tumor cells show repeated DNA sequences of abnormal length-involves microsatellite instability (MSI)
In-frame mutation
-mutations that involve more than one base of DNA and do not change the reading frame, but do impact the resulting protein by removing or adding one or more amino acids
therapeutic range of warfarin
-narrow -target INR: 2.0-3.0 (2.5)
risk factors for breast cancer
-nationality -age- uncommon before menopause -positive family history -early menarche- before age 12 -late menopause- after age 55 -atypical epithelial hyperplasia of breast on biopsy -hormone replacement therapy -radiation exposure to breasts before age 30 -lifestyle- physical activity and weight management reduce risk -alcohol use
what are the aspects that must be covered in informed consent for genetic testing?
-nature/scope of test -benefits -limitations -risks -costs
how many cases of sudden childhood death are caused by long QT syndrome annually?
-nearly 4000
Autosomal Recessive Inheritance
-need 2 recessive genes to get disease -if you have one person with a recessive gene and the other does not, the offspring may be a carrier of the disease -transmitted to males and females equally -usually skips a generation, but not always
slow acetylators
-need less drug
fast acetylators
-need more drug
single gene neurologic disorders
-neurofibromatosis -lysosomal storage disorders (hunters, Tay-Sachs, Fabry, Gaucher) -Triplet Repeats (Fragile X, Huntington's)
x-linked recessive diseases
-never transmitted from father to son -more disease conditions seen in male than female -girls are more likely to be carriers or only show mild symptoms
what is the most widely used genetic screening?
-newborn screening -bloodspots on filter paper -public health initiative- formal consent not usually obtained
are the normal and abnormal cells in mosaicism and x-inactivation evenly distributed in all tissues?
-no
do polygenic disease have anything to do with the environment?
-no
has a de novo mutation for huntingotns ever been reported?
-no
if dad has permutation for fragile X syndrome, will the daughter get the full disease?
-no
is monosomy that occurs in autosomes compatible with life?
-no
is the genotype/phenotype correlation perfect in G6PD Deficiency?
-no
is the homozygous state of achondroplasia compatible with survival?
-no
are multifactorial and polygenic the same?
-no -multifactorial might be polygenic or might have to do with other things that are in the environment that are affecting the gene (ex- uterus) -polygenic just means that multiple genes are involved
is pentrance always complete?
-no -sometimes variable- called incomplete penetrance; cannot predict penetrance
average risk- family history risk assessment for complex cardiac diseases
-no affected relatives -only one affected 2nd degree relative from one or both sides of pedigree -no known family history -adopted individual with unknown family history
osteogenesis imperfecta type II
-no normal collagen produced -most severe form -bone fractures and skeletal malformations occur in prenatal period and are lethal -mean bone width and length are below 50th percentile -20% are still born -90% die in 4 weeks
requirements for populations to stay in hardy-weinberg equilibrium
-no one migrates -people mate randomly -population is extremely large -everyone has children -there are no mutations
requirements for populations to stay in Hardy-Weinberg Equilibrium
-no one migrates -people mate randomly -the population is extremely large -everyone has children -there are no mutations
is Hardy-Weinberg Equilibrium likely?
-no, almost impossible
is cancer considered inherited if it happens in the elderly?
-no, it is expected in this population -considered inherited if it happens in younger people
can body cells divide indefinitely?
-no- only a limited number of times -body cells are not immortal
what form of congenital adrenal hyperplasia is more prevalent?
-non-classic forms such as mild CAH
introns
-non-coding portions
what do numerical mutations usually occur as the result of?
-nondisjunction
nuclear DNA vs mitochondrial DNA
-nuclear DNA inherited from mother and father (23/parent, 46 total) -mitochondrial- inherited only from mother (1 chromosome total, visualized as circle) -mitochondrial DNA is circular and nuclear DNA is linear -both are double stranded
bases-DNA
-nucleoproteins created from the proteins we eat -may be single-ring structures (pyrimidines) or double-ring structures (purines) -these bases form the essential element of nucleic acids
what is there a direct correlation between in familial hypercholesterolemia?
-number and activity of functioning LDL receptors -the number and activity of functioning LDL receptors, levels of serum LDL cholesterol, and he age of onset and severity of the resulting atherosclerosis
what does the number of receptor cells mean?
-number varies from person to person -those with higher receptor cells will have a greater response to an agonist -lesser response to antagonist
aneuploidy
-numerical chromosomal defect caused by defect in the replication and distribution of the chromosomal material during cell division
germ-line mutation
-occurs directly in the sperm or egg or in precursor cell that produces gametes -if mutant gamete participates in fertilization, then offspring will contain mutation
Germ-line mutation
-occurs directly in the sperm or the egg -if mutant gamete participates in fertilization, then offspring will contain mutation -hereditary mutation -comes from mom and dad
DNA synthesis checkpoint
-occurs during synthesis phase (S) -checks whether DNA has been replicated correctly -if so, the cell continues on to mitosis
mitosis checkpoint
-occurs during the mitosis phase (M) -checks whether mitosis is complete -if so, the cell divides and the cycle repeats
meiosis
-occurs only during gamete formation -meiosis 1- chromosomal number is reduced to a haploid number (one complete copy of each chromosome) in the resulting daughter cells -meiosis II- daughter cells split into 2 more haploid gametes
cell growth checkpoint
-occurs towards the end of the growth phase 1 (G1) -checks whether the cell is big enough and has made the proper proteins for the synthesis phase -if not, the cell goes through a resting period (G0) until it is ready to divide
population bottleneck
-occurs when a large population is drastically reduced in size -rebounds in population size occur with descendants of a limited number of survivors
non-random mating
-occurs when certain individuals contribute more to the next generation than others
predictive genetic testing
-offered to asymptomatic individuals based on their family history -types: pre symptomatic/ predispositional
X-linked recessive inheritance
-often see a skip in generation -usually only seen in males -no X-linked disease ever gets passed to sons from daughters- only daughters, and they will be carriers
what increases the risk of down syndrome?
-older age of mother (40)
when has retinoblastoma been found?
-on ultrasound during 3rd trimester
probably diagnosis of fragile X tremor ataxia syndrome
-one major neuroradiologic sign and one minor clinical sign OR two major clinical signs
inheritance
-one of the most common autosomal recessive disorders in whites -most common lethal monogenic disease
incidence of cystinurea
-one of the most common errors in amino acid transport -1 in 7000
cystinurea
-one of the original inborn errors of metabolism -amino acids are readily filtered by the glomerulus and undergo nearly complete reabsorption by proximal tubular cells -a defect results in failure of reabsorption
what does early onset alzheimers involve mutations in?
-one of three known genes: APP, PSEN1, PSEN2
discordance of GINA and Patient Protection and Affordable Care Act (PPACA)
-one provision in PPACA enables employers to tie health insurance costs with employee participation in wellness programs -some programs are mandatory; may include disclosure of family health history to receive incentive -legislation introduced March 2015- "Preserving Employee Wellness Programs Act"
what happens if nondisjunction occurs in a secondary spermatocyte during meiosis II
-only 2 of the 4 sperm will be abnormal and only 2 of the zygotes will be chromosomal abnormal -the other 2 will be normal euploids
how many genes are expressed?
-only a subset -varies according to the type of cell
what does each nucleated cell contain?
-only the same DNA
genetic effect of population bottleneck
-only those individuals who survive can reproduce -only their traits can be passed on -new population loses some genetic diversity
changes in histone/DNA structure may result in what?
-open chromatin and transcriptional activation -condensed chromatin and transcriptional repression -core histone proteins being replaced by other variations
what might changes in histone structure result in?
-open chromatin and transcriptional activation -condensed chromatin and transcriptional repression -core histone proteins being replaced by other variations
RET gene- Hirschsprung disease
-originally identified as a photo-oncogene, encoding a receptor tyrosine kinase -RET mutations in Hirschsprung disease tend to be inactivating or loss-of-function mutations
where do cancers originate? what do they result from?
-originate in a single cell -result from a progressive accumulation of mutations -often in genes necessary for DNA maintenance and repair -cell lineage then divides without constraint -normal cell metabolism profoundly altered and cells may obtain the ability to infiltrate other tissues and metastasize to other organs
what do people with retinoblastoma have an increased risk for?
-other cancers, especially of pineal gland, osteosarcoma, muscles, and melanomas
how many DNA probes are used with FISH? what is the cost per probe?
-over 40 -$200
treatment of sickle cell disease
-oxygenation, opioids, fluids to treat pain crisis -penicillin -hydroxyurea -blood transfusions -preventing complications -blood and bone marrow stem cell transplant -gene therapy -new meds
1st degree relation
-parents -siblings -children
chromosomal mutations and examples
-part or whole chromosome is missing, duplicated, or translocated -trisomy 21, chronic myelogenous leukemia
testing for chromosomal disorders- description of disorders, examples, and types of tests
-part or whole chromosome missing, duplicated, or translocated -Trisomy 21, CML -Karyotyping, PCR
what can mapping a trait geographically suggest?
-patterns of migration
prenatal genetic testing
-performed during pregnancy to assess the health status of the fetus -offered when there is increased risk
preimplantation genetic testing
-performed on early embryos resulting from in vitro fertilization
karyotype-cytogenic testing
-performed on lymphocytes in metaphase arranged and analyzed by the computer -can be performed on almost any tissue- amniotic fluid, bone marrow, placenta -detects aneuploidy, rearrangements, translocations, large deletions, and duplications from 100 to 10 mega bases (100 million to 10 million bases)
key indicators for hereditary nonpolyposis colorectal cancer (HNPCC)
-personal history of colorectal or endometrial cancer diagnosed before age 50 -first-degree relative with colorectal cancer diagnosed before age 50 -two or more relatives with colorectal cancer or an HNPCC-associated cancer, which includes endometrial, ovarian, gastric, hepatobiliary, small bowel, renal pelvis, or ureter cancer. The one relative must be the first-degree relative of the other -colorectal cancer occurring in 2 or more generations on the same side of the family -a personal history of colorectal cancer and a first-degree relative with adenomas diagnosed before age 40 -an affected relative with a known HNPCC mutation
what do homogeneous and heterogeneous have to do with?
-phenotype
osteogenesis imperfecta types II, III, and IV
-phenotype depends on the position of the glycine amino acids substitution
ehlers-danlos syndrome
-phenotype varies; 6 major types -classic: autosomal dominant caused by a chain mutations of type V collagen (A1 and A2)
Type II and Type III hyperphenylalanemia
-phenylalanine is elevated -phenylalanine-restricted diet does not spare individual from neurologic deterioration
how are individuals with PKU Type 1, or classic PKU, treated?
-phenylalanine-restricted diet
what inherited defects result from problem with the amino acid phenylalanine?
-phenylketonuria -albinism -tyrosinemia -alkaptonuria -all recessive
what is the oncogene that results from the translocation in CML called?
-philadelphia chromosome t(9; 22)
Molloy vs. Meier
-physician should have performed a diagnostic genetic test on a child with cognitive impairment to see if the child had a genetic condition -two children with Fragile X -first child should have been tested
Pate vs. Threlkel
-physician sued for not warning patient's daughter of her genetic risk for thyroid cancer -daughter diagnosed with advanced thyroid cancer -claimed she would have had early diagnosis if she had known the risk -result- physician duty to tell patient to warn her daughter
chromosome translocation
-piece on one chromosome is transferred to another
what infection are people with sickle cell anemia especially at risk for?
-pneumonia
types of mutations of normal genes
-point mutations -chromosome translocation -gene amplification
complex heart disease
-polygenic -family history improves risk prediction -current genetic markers do not improve risk prediction -genetic markers have been associated with coronary artery calcification -9p21.3 associate with coronary artery disease
types of CYP population phenotypes
-poor metabolizer (PM) -Intermediate Metabolizer (IM) -Extensive Metabolizer (EM) -Ultra-Rapid Metabolizer (UM)
codeine and poor metabolizers
-poor metabolizers fail to convert codeine to morphine and therefore receive little therapeutic benefit
codeine in poor metabolizers
-poor metabolizers fail to convert codeine to morphine and therefore receive little therapeutic benefit
clinical implications of sickle cell anemia
-poor perfusion and oxygenation results in fatigue, pain, organ damage (strokes, eye, gallstones, lungs, liver, kidneys), increased infections
malformation
-poor tissue formation
Maple sugar urine disease (MSUD)
-potentially deadly disorder that affects the breakdown of three amino acids: leucine, isoleucine, and valine -they are normally broken down by six proteins that act as a team to form a complex called branched -chain alpha-ketoacid dehydrogenase (BCKD) -most common defect is caused by a mutation in a gene on chromosome 19 that encodes the alpha subunit of the BCKD complex (BCKDHA)
example of a disorder that can be detected by FISH testing
-prader-willi's
genetic testing of an asymptomatic woman whose sister is positive for the mutation that is responsible for autosomal dominant disorder that has a 70% penetrance rate would fall into which testing category?
-predictive predisposition
premature disease onset concepts for interpretation of a family history- complex cardiac diseases
-premature coronary artery disease: <55 in males, <65 in females -premature stroke and type 2 diabetes: <50 years
rare cardiac disease red flags- mendelian cardiac disease
-premature death before age 50 caused by heart disease in 1 or more relatives -disability from heart disease in close relative age 50 or younger -specific knowledge of certain cardiac condition in a relative (HCM, DCM, LQTS, arrhythmia, Marfan) -history of drowning or single car accident
high risk- family history risk assessment for complex cardiac diseases
-premature disease in 1st degree relative -premature disease in a 2nd degree relative (CAD only) -two affected 1st degree relatives -1st degree relative with late/unknown onset of disease and an affected 2nd degree relative with premature disease from the same lineage -two 2nd degree maternal or paternal relatives with at least one having premature onset of disease -three or more affected maternal or paternal relatives -presence of moderate risk family history on both sides of the family
red flags for common cardiac disease- complex cardiac diseases
-premature disease in close relatives -multiple family members affected -disease in the absence of risk factors -multiple, related conditions
key family history concepts- interpretation of family history- complex cardiac diseases
-premature disease onset -degree of relation
definitive diagnosis of fragile X tremor ataxia syndrome
-premutation -white matter lesions -with either intention tremor or gait ataxia
cardiac disease red flag- complex cardiac diseases
-presence of congenital heart defect -particularly left ventricular outflow tract obstructions (LVOTO) (e.g. hypo plastic left heart syndrome)- hypo plastic left heart syndrome has a 20% recurrence risk for some form of congenital heart disease and increased risk of bicuspid aortic valve in relatives
PSEN1 gene- alzheimers
-presenilin 1 at chromosome 14q24.3 -codes for a protein localizing the endoplasmic reticulum -leads to impaired mitochondrial function, formation of reactive oxygen species, and increased vulnerability to apoptosis -70% FAD shows linkage to this locus
incidence of factor V Leiden
-present in 2-5% of asymptomatic white and 1.2% of black population -greece and southern sweeten- rates above 10%
Celexa (Citalopram)
-primarily metabolized by CYP3A4 and CYP2C19 -inhibitors of 3A4 (ketoconazole, itraconazole, and macrolide antibiotics) and CYP2C19 (like omeprazole) might decrease clearance of celexa -co-administration of celexa and potent CYP3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram
ultra-rapid metabolizers
-processes drug more rapidly -standard dosing may be ineffective
poor metabolizers
-processes drug more slowly than expected -at increased risk for side effects and toxicity -standard dosing is too high
chromosome mutations
-produce chromosome aneuploidy -most common mutations: 7/1000 births -many lost to spontaneous abortions
huntington disease
-progressive disorder of motor, psychiatric, and cognitive functions resulting from selective neuronal death -mean survival time after onset of symptoms is 15-18 years -no cure
osteogenesis imperfecta type III
-progressive kyphoscoliosis and skeletal abnormalities -early onset fractures- present at birth -osteopenia leads to poor longitudinal growth- <3rd percentile -blue sclera -1/3 survive long term
signs and symptoms of hemophilia B
-prolonged, spontaneous, hemarthrosis, deep muscle bruising, intracranial bleeding at birth -unexplained GI bleeding -excessive bruising -mild to severe
clinical characteristics of down syndrome
-prominent forehead -flattened nasal bridge -habitually open mouth -projecting lower lip -protruding tongue -slanting eyes -epicanthic folds -white or light yellow cloud-like specs may circumscribe the outer layer of the iris (Brushfield spots)
treatment of MSUD
-prompt -carefully controlled diet -synthetic formula provides nutrient and all the amino acids except leucine, isoleucine, and valine- added in limited amounts -careful monitoring of protein intake and close medical supervision for life -sick day care -liver transplant
phases of mitosis
-prophase -metaphase -anaphase -telophase
Heritability
-proportion (%) of phenotypic variation explained by genetic variation -range: 0-1 (0-100%)
phenotype frequencies
-proportion of individuals in a population that express a particular phenotype
prevalence
-proportion of people who have a particular disease at a specific time over a specific amount of time
number of genes shared in identical twins
-proportion: 1 -100%
number of genes shared between first-degree relatives, parent-child, siblings
-proportion: 1/2 -50%
number of genes shared in fraternal twins
-proportion: 1/2 -50%
number of genes shared between second-degree relatives, grandparent-grandchild, uncle-nephew, aunt-niece
-proportion: 1/4 -25%
number of genes shared between third-degree relatives, first cousins
-proportion:1/8 -12.5%
telomeres
-protective caps on each chromosome that are held in place by a telomerase -telomeres become smaller and smaller with each cell division -cancer cells can activate telomeres, leading to continued division
what might happen if chromatin structure is altered, such as a more open or relaxed structure?
-protein factors might bind to promoter or other regulatory sequences to begin transcription
role of general nurse in genomic care
-providing accurate information -ensuring appropriate referral -serving as patient advocate -maintaining confidentiality
manifestations of cystic fibrosis
-pulmonary, GI, and reproductive problems and elevated Cl in sweat (>60 mEq/L)
expressivity
-range of phenotypes expressed by a specific genotype -always an individual issue rather than population -degree of gene expression can vary by person, some more severe than others
expressivity
-range of phenotypes expressed by a specific genotype -if you have a group that all has the same genotype, they may have different symptoms -some can be mild, some severe -range of phenotypes- genes will be the same
rapid Fish panel
-rapid FISH panel may remain with probes directed at 13, 18, 21, X and Y- allows for 24 hour diagnosis for timely management
incidence of homozygous familial hypercholesterolemia
-rare -1:1 million born with complete absence of functional receptors
homozygous familial hypercholesterolemia
-rare -demonstrate severe hypercholesterolemia (600-1000 mg/dL; normal, 150-230 mg/dL) at birth and develop raised, yellowish, cutaneous xanthomas by age 4
inheritance and penetrance of Jervell and Lange-Nielsen syndrome- long QT
-rare, autosomal recessive form -incomplete penetrance found in heterozygous state, parents of a child with JLN syndrome are asymptomatic
what should be included in anticipatory guidance- importance of pre-test counseling
-reasonable expectations -if we find CNV, not necessarily abnormal -may need parental testing -availability of formal genetic counseling -may need formal genetics/dysmorphology evaluation -logisitics- who will call with results
treatment of Fabry disease- lysosomal storage disease
-recombinant A galactosidase
treatment of Gauncher disease- lysosomal storage disease
-recombinant analog for B-glucocerebrosidase in types 1 and 3 are sufficient -type 2 has no serious treatment and has serious brain involvement
hemophilia B
-reduction of factor IX -due to hundreds of different missense, nonsense, frameshift, and deletion mutations
pharmacogenetics
-refer to the effects of single gene variations -first used in 1950s
pharmacogenomics
-refers to genome wide effects -single genes do not work in isolation
pharmacogenetics
-refers to the effects of single gene variations -first used in 1950s
RNA splicing
-regulated by splicesosomes -abnormal splicing can be relatively common cause of disease -alternative splicing can increase functional variation in cells
what is the normal function of RB1 gene? retinoblastoma
-regulates the cell cycle at the G1 to S transition -RB gene product prevents transcription factors from enhancing cell division
clinical applications of pharmacogenetics
-research the pharmacogenetics of medications -know what precautions may need to be taken for those individuals who may be poor or fast metabolizers -identify the genetic pathway that alters the pharmacokinetic or pharmacodynamic processes -identify drug to drug interactions
ethical goals of clinical genetics
-respect patient autonomy -non-directive and supportive counseling -assist families in making an informed decision
ethical goals of clinical genetics
-respect patient autonomy -non-directive and supportive counseling -assisting families in making an informed decision
what does disease progression of DMD lead to?
-respiratory muscle weakness and cardiomyopathy -most patients die by age 20
CYP2D6
-responsible for metabolism of 25-30% of drugs -phenotype varies with ethnicity
CYP3A
-responsible for metabolism of about 50% of medications -grapefruit juice is enzyme inhibitor -st. John's Wort is enzyme inducer -inconsistent genotype/phenotype concordance
caretaker genes
-responsible for the maintenance of genomic integrity -loss of function of these leads to increased mutation rates -encodes proteins involved in repairing DNA such as errors in DNA replication, mutations caused by UV or ionizing radiation, and mutations caused by chemicals and drugs
sporadic cancer
-result of environmental exposure -no observable pattern of inheritance can be identified, not generally present in higher levels than expected, not passed to offspring -usually cancers of somatic cells -most significant environment that can cause this- in utero
chronic myeloid leukemia
-results from a balanced reciprocal translocation t(9,22) -relocates the ABL proto-oncogene from 9q to 22q where it is positioned with the BCR cluster -results in a novel protein with enhanced tyrosine kinase activity that triggers runaway cell activity (neoplasia)
chronic myeloid leukemia (CML)
-results from a balanced reciprocal translocation: t(9;22) -relocates the ABL photo-oncogene from 9q to 22q where it is positioned with BCR cluster -results in a novel protein with enhanced tyrosine kinase activity that triggers runaway cell activity
spontaneous mutations
-results from abnormalities in biological processes -underlying causes originate within the cell
Maternal PKU
-results from lack of PAH in the liver and placenta that ordinarily would convert excess phenylalanine to tyrosine -concerning because of possible toxicity to fetus -may occur when mother forgets the special diet she had as a child or does not tell physician she has PKU child can be inversely affected even if they do not carry the genetic mutation
pros of using PCR testing
-results in less than a day -less expensive than southern blot -requires less DNA but shorter stretches of DNA are analyzed
protected genetic information
-results of one's own genetic tests and those of family members -any clinical signs of a disease in a family member -whether you or your family have requested genetic services
what is considered protected genetic information?
-results of one's own genetic tests and those of family members -any clinical signs of a disease in a family member -whether you or your family have requested genetic services
what are the sections when collecting a family history?
-risk assessment -inform diagnosis -disease management -build rapport
what is the risk for G6PD Deficiency?
-risk hemolytic anemia -especially if exposed to antimalarials, aspirin, probenecid, vitamin K, or if they eat fava beans (favism)
age- risk factor for prostate cancer
-risk increases over age 55 -75% of cases are diagnosed after age 65
clinical implications for factor v leiden
-risk of venous thrombosis is increased 3-8x in heterozygous individuals, 30-140x in homozygous -probability of thrombosis before age 33 is 44% in homozygous and 20% in heterozygous -accounts for 40% of idiopathic venous thromboembolic disease
B thalassemias
-second most common cause of hypochromic, microcytic anemia -gene is present but there is a defect in transcription, mRNA processing, or translation -only 2 b genes -affects the size of the cell -cause hypochromic (low hemoglobin) and microcytic (small cells)
PSEN2 gene- alzheimers
-second presenilin located at chromosome 1q31 -less than 5% of FAD cases
where do you find detailed information on available drug interaction data when looking online?
-see drug interactions under precautions section
Jervell and Lange-Nielsen (JLN) syndrome- long QT syndrome
-sensorineural hearing loss, QT prolongation, sudden syncope starting in early childhood -autosomal recessive inheritance
what RNA sequences are generally transcribed but not translated in protein
-sequences before the first exon and after the last exon
signs and symptoms of PKU
-severe cognitive impairment -small stature -small head size -poor motor skills -light skin, hair, eye color -tremors and seizure activity -musty or mousy odor of sweat, breath, urine
signs and symptoms of phenylketonuria (PKU)
-severe cognitive impairment -small stature -small head size -poor motor skills -light skin, hair, eye color -tremors and seizure activity -musty or mousy odor of sweat, breath, urine
half siblings- pedigree
-shared parent in middle with line connecting to current and former spouse on either side -line from each connecting children
microRNA (miRNA)
-short post-transcriptional regulators that bind to target messenger RNA, most commonly resulting in gene-silencing -bind to complementary strands of messenger RNA, preventing the functional protein from being formed
types of hirchsprung
-short segment -long segment
symptoms of Turner syndrome
-short stature -infertile -female -normal intelligence
other neurologic findings of fragile X tremor ataxia syndrome
-short term memory loss -executive function deficits -cognitive decline -dementia -parkinsonism -peripheral neuropathy -autonomic dysfunction -lower limb proximal weakness
IVF ethical issues
-should they be implanted? -when should they be destroyed? -who should pay for their storage? -should they be donated to other couples? -legal implications- divorce or death -questions about human stem cell research -religious influences
alzheimers disease
-shrinkage of brain tissue caused by degeneration and death of neurons -sulcus are wider; gyrus shrinks, ventricles enlarge -memory fades when cells of hippocampus degenerate -as disease progresses through cerebral cortex, judgement declines, emotional outburst occur, and language is impaired
example of missense mutation
-sickle cell anemia -portion of protein in red blood cells: Val-His-Leu-Thr-Pro-Glu-Glu -portion of protein in sickled red blood cells: Val-His-Leu-Thr-Pro-Val-Glu
GINA
-signed into law on May 21, 2008 -federal protection against genetic discrimination in employment and insurance
GINA
-signed into law on May 21, 2008 -federal protection against genetic discrimination in employment and insurance -cannot use genetic information to make decisions about eligibility, the size of premiums, or extent of coverage -cannot use genetic information as evidence of pre-existing condition -cannot require that a client have genetic testing -illegal for employers to use genetic information to make decisions about hiring, promotions, or termination of employment
warfarin
-significant inter-individual dose-response -life threatening consequences
what does loss of 1 a gene cause in alpha thalassemia? 2? 3? 4?
-silent mutation -trait -hemoglobin H -hydrops fetalis- fatal
why do people often think patients with OI are abused?
-similar symptoms -bruising, unexplained fractures, evidence of old fractures in various stages of healing -need thorough family history and careful physical exam
familial hypercholesterolemia
-single gene disorder due to mutations in LDLR gene; 19p13.1-13.3 -variable phenotype -more than 1000 mutations disrupt LDLR function
what is the major disadvantage of the FISH method of genetic testing?
-single nucleotide mutations cannot be detected
SNP- schizophrenia
-single nucleotide polymorphism -most common type of genetic variation among people -each SNP represents a difference in a single nucleotide -ex- replaying cytosine with thymine, etc.
anaphase- mitosis
-sister chromatids separate -centromeres divide
receptors
-sites on a cell surface or within a cell where substances can bind and control cell function
wormian bones
-skeletal anomaly -irregularly shaped bones within the sutures of the skull -associated with severe congenital disorders
3 of what 4 criteria need to be met for someone to be diagnosed with ehlers-danlos syndrome?
-skin hyper extensibility -wide strophic scars -joint hypermobility -positive family history
where is the major site of drug absorption?
-small intestine
microevolution
-small steps of genetic change that shift allele frequencies in a population
common variant polymorphisms- complex cardiac diseases
-smaller effects -don't typically change gene function enough to cause disease alone -combined with other gene variants and environmental factors may cause disease -found in common complex cardiac diseases
what cells are involved in cancer?
-somatic cells
is skin cancer a somatic or germ-line mutation?
-somatic mutation -not passed on from parents
p53 protein
-somatic mutations of TP53 found in half of all human cancers -maps to 17p and codes a transcription factor expressed when cell is stressed (ex- virus, toxin, radiation) -mediator or guardian of the genome- up regulates to preserve the integrity of the genome by inhibiting tumor formation -if unable to respond to excess damage, then p53 triggers apoptosis and promotes cell death
p53 protein
-somatic mutations of p53 are found in half of all human cancers -maps to 17p and codes a transcription factor expressed when cell is stressed (e.g. virus, toxin, radiation) -mediator or guardian of genome- up regulates to preserve the integrity of the genome by inhibiting tumor formation -if unable to respond to excess damage, then p53 triggers apoptosis- promotes death
why are some people never diagnosed with mild CAH?
-some can mount limited glucocorticoid stress responses and thus are never recognized as having the disorder
relationship between some people with mild CAH and illness
-some have frequent illnesses and decompensated when challenged by common infections and minor trauma
Polymerase Chain Reaction (PCR)
-specific DNA sequences are copied many times to yield large quantities of that particular DNA portion corresponding to a certain gene -provides exact repeat number -need to know what area to amplify -often used in forensics
two major classes of lysosomal storage disorders
-sphingolipidoses -mucopolysaccharidoses
what does triploidy usually result in?
-spontaneous abortion or stillborn death
what do most cases of unilateral MRD undergo? what is MRD associated with?
-spontaneous involution -associated non renal malformations
what are the goals of treatment for retinoblastoma? what does treatment depend on?
-stop the cancer, then save the vision -tumor stage, unilateral or bilateral, localization and size of tumor, age of child
management of PKU
-strict dietary restriction of phenylalanine intake (less than 300-500 mg daily) -drug therapy- sapropterin (Kuvan)- improves conversion of phenylalanine to tyrosine
rare variant "mutations"- mendelian cardiac diseases
-strong effects -can change gene function enough to cause disease -found in Mendelian cardiac disease
histone modification
-structure of the histone influences gene expression -chemical modification may occur through methylation, acetylation, or phosphorylation
alzheimers and epigenetics
-studies of human postmortem brain demonstrate that aging and Alzheimers are associated with epigenetic dysregulation -early exposure to toxins can alter methylation patterns of genes involved in Alzheimers that affect brain development, leading to observations seen later during the disease -twin studies also suggest that epigenetic mechanisms mediate the risk for Alzheimers
genomics
-study of all genes in human genome, including interactions with each other, the environment, and the influence of other psychosocial and cultural factors
treatment of familial adenomatous polyposis (FAP)
-subtotal colectomy leaving rectum intact followed by periodic sigmoidoscopy
what is lactose? how is it normally processed by the body?
-sugar found in milk -normally cleaved to form glucose, which is used for energy, and galactose -GALT normale binds to galactose and converts it to glucose, which is used for energy
drugs that go through acetylation
-sulfamethoxazole -hydralazine -procainamide -isoniazid -caffeine
Apolipoprotein E gene (APOE)- alzheimers
-susceptibility (not casual) gene located on chromosome 19q13.2 -predisposes to late onset alzheimers -critical role in triglyceride rich lipoprotein metabolism and cholesterol homeostasis -originally known risk factor for CVD -3 variant alleles with 5 common genotypes -E3 allele increases risk and decreases age of onset
initial s/s of hunters disease
-swollen abdomen -facial features -hernias -can suggest other problems and lead to delayed diagnosis
transcription
-taking the DNA, splitting it, then it gets read and translated into messenger RNA -when it gets transcribed into mRNA, adenine now pairs with uracil -no tyrosine -in the nucleus, the cell's machinery copies the gene sequence into mRNA, a molecule that is similar to DNA
translation
-taking the code from the RNA and using it to make amino acids -amino acids and proteins- terms used interchangeably -the protein-making machinery, the ribosome, reads the mRNA sequence and translates it into the amino acid sequence and translates it into the amino acid sequence of the protein
acetylation tags- histones
-tend to unwind DNA and activate genes
what do males with CAH have an increased incidence of
-testicular adrenal rest tumors (TARTs), which are benign hyperplasias rather than true tumors
genetic testing for familial adenomatous polyposis (FAP)
-tests for mutations of APC gene -positive in 85% of families with FAP
heterogeneous
-the 2 alleles are different
what is the main benefit of the human genome project?
-the ability to better diagnose, treat, and prevent disease
monosomy
-the absence of an entire chromosome -occurs when a sperm fertilizes an egg lacking a chromosome after nondisjunction occurs
trisomy
-the addition of an entire chromosome
what does the DNA code of a gene directly determine?
-the amino acid sequence of a protein
what does the DNA coding of a gene directly determine?
-the amino acid sequence of a protein -the amino acid sequence of a protein defines the end-product, which can be, for example, an enzyme or a hormone
pharmacodynamics
-the body responses induced by a drug -can be influenced by genetic differences
pharmacodynamis
-the body responses induced by a drug -can be influenced by genetic differences
acrocentric chromosomes
-the centromere that holds the two chromatids together is nearly terminal in position
genetic drift
-the change in allele frequency -population becomes less diverse -future generations are more like people who had lots of children than people who had few children- can be due to migration or natural disaster
what can any mutation influence?
-the character and function of the protein formed, independent of the mode of inheritance
relationship of individuals to the number of shared genes
-the closer the relationship between two individuals, the greater the number of shared genes -more risk of disorder
gene pool
-the collection of all alleles in the members of the population
what is the consequence of cystinurea?
-the consequence of increased and insoluble cystine in the urinary tract is the formation of renal stones- nephrolithiasis
what does alpha thalassemia result from?
-the deletion of one or more of the 4 a genes located on chromosome 16 -each gene is responsible for 25% production of alpha chains
alternative splicing
-the differential joining of exon to form more than one variant of the same gene
natural selection
-the differential survival and reproduction of individuals with a particular phenotype
what does the amino acid sequence of a protein define?
-the end-product which can be, for example, an enzyme or a hormone
what does multifactorial inheritance have a lot to do with?
-the environment -the greatest environment that we have is the uterus -multifactorial diseases often occur before we are even born
what does the presence of few alleles mean?
-the gene has been highly conserved over hundreds of years
what does the presence of hundreds of alleles mean? what is an example of this?
-the gene has been less stringently conserved -the gene responsible for cystic fibrosis, which may have one or more of 1500 reported changes or mutations
what does it mean if a gene is differentially expressed?
-the gene is expressed during some periods, but not during others -ex-genes not expressed until puberty
characteristics of multifactorial inheritance
-the greater the number of predisposing risk genes possessed by the parents, the greater the probability that they will have an affected child -recurrence risk is higher when more than one family member is affected -risk increases with severity of malformation
characteristics of multifactorial inheritance
-the greater the number of predisposing risk genes possessed by the parents, the greater the probability that they will have an affected child -risk to relatives declines with increasingly remote degrees of relationship -recurrence risk is higher when more than one family member is affected -risk increases with severity of the malformation -where a multifactorial condition exhibits a marked difference in incidence with sex, the less frequently affected sex has a higher risk threshold and transmits the condition more often tot he more frequently affected sex
what is the complete set of genes for our species called?
-the human genome
what happens after the initial transcription of DNA into mRNA is complete?
-the introns must be spliced out in order for the mature mRNA to contain only the correct sequence for the amino acids that belong in the proteins -the exon must then be connected together to form the mature mRNA -the spliced out introns are actually exon for the different gene within the coding region
what does the severity of B thalassemia depend on?
-the level of gene expression -can be minor, intermediate, or major
translocation
-the movement of genetic material between chromosomes
penetrance
-the number of people that get a certain disease out of the population with the genotype for the disease
transcribed or template DNA strand
-the one strand out of the 2 that make up DNA that serves as the genetic code
what constitutes the code for the amino acid sequence of a protein?
-the order of the bases in the DNA
penetrance
-the percentage of individuals of a specific genotype showing the expected phenotype -the percentage of people who have the phenotype for a disease out of a group of people who all have the genotype
personalized medicine
-the practice of tailoring prevention and disease management activities for individuals based on genomic characteristics
transcription
-the process where the DNA sequence of a gene is recognized and the DNA is used as a template to make a copy of messenger RNA (mRNA)
what happens to the chromatids if nondisjunction occurs during meiosis II?
-the result is two chromatids that originated from the replication of the same DNA strand and one unique chromatid occurring in the fertilized egg
how does a ribosome read the mRNA and make a protein?
-the ribosome starts at the sequence AUG, then reads three nucleotides (one codon) at a time -each 3-nucleotide codon specifies a particular amino acid -the stop codons (UAA, UAG, UGA) tell the ribosome when the protein is complete
where do poorly absorbed drugs remain?
-the stool
epigenetics
-the study of changes in gene activity that do not involve alterations to the genetic code but that are still passed to successive generations -environmental factors such as diet, stress, and prenatal nutrition imprint genes passed from one generation to another
cytogenetics
-the study of chromosomal abnormalities
population genetics
-the study of the genetics of a population and how the alleles vary or stay the same over time
what is true about genes, DNA, and chromosomes?
-they are all different forms of the same substance
why can adenine and cytosine not form a normal complementary base pari even though one is a purine and one is a pyrimidine?
-they do not have the same number of areas that can be connected by hydrogen bonds
what happens to all daughters of males affected by an x-linked recessive disease?
-they will all be carriers
Romano-Ward syndrome- long QT syndrome
-those affected have normal hearing -autosomal dominant transmission -QT prolongation -sudden syncope starting in early childhood
when are the greatest consequences of nondisjunction observed? why?
-those observed in meiosis -because the resulting embryo has too many or too few chromosomes
codons
-three bases of mRNA that code for an amino acid
types of APOE genes
-three variant alleles with 5 common genotypes -E4 allele increases the risk and decreases age of onset of alzheimers
additional symptoms of permutation females- fragile X primary ovarian insufficiency
-thyroid dysfunction -migraines -learning disabilities -anxiety -fragile x tremor ataxia syndrome
when is FISH testing most likely to be used?
-to determine the carrier status of a child whose sister has cystic fibrosis
PKU
-too much phenylalanine -toxic if too much -tested for with newborn screening -autosomal recessive inheritance
reciprocal translocations
-translocations that exchange material between two chromosomes -usually have little consequence for the individual -become important during formation of gametes and segregation of chromosomes- some gametes will receive extra copies of genetic material while others will be missing genetic material
treatment of sickle cell anemia
-treat pain crisis: fluids, oxygenation, opioids -penicillin -hydroxyurea -blood transfusions -blood and marrow transplant -gene therapy -new meds
pregnancy loss/spontaneous abortion- pedigree
-triangle -includes number of weeks, if known
triplet repeat expansion mutations and examples
-trinucleotide repeats -fragile X associated disorders
testing for triplet repeat expansions- description of disorders examples, and types of tests
-trinucleotide repeats -fragile X associated disorders -PCR; DNA testing for repeats, methylation analysis
what kind of disorder is fragile X? what is another example of this kind of disorder?
-triplet repeat -huntingtons
nonmendelian inheritance
-triplet repeats -genomic imprinting -mitochondrial -multifactorial
most common autosomal trisomy found in abortuses
-trisomy 16 -1/3 -shows little association with increasing maternal age
what is the cause of 40-50% of first-trimester spontaneous abortions?
-trisomy for one of the autosomes
T or F: a female carrier of fragile X syndrome has a 50% chance of passing the mutated gene on to her children with each pregnancy
-true
T or F: the gene for fragile X is located on the long arm of the X chromosome
-true
male nondisjunction (meiosis 1)
-turner syndrome
most common form of OI
-type 1
types of vWD
-types I, II, III
types of vWD
-types I, II, and III
what are the severe forms of OI?
-types II and III
onset and prevalence of alzheimer disease
-typically late onset disorder- after age 65 -present in 2% of population over 65; 8% over 85 -prevalence lower than expected due to competing causes of death
what does PKU lead to a deficiency of?
-tyrosine
imatinib Mesylate (Gleevec)
-tyrosine kinase inhibitor -prevents the growth inducing signals by binding to the ATP binding sites of the enzyme
Menkes syndrome
-unable to get copper out of enterocytes -ceruloplasmin has no copper to transport -results in copper deficiency
ultra rapid drug metabolizer
-unbalanced -greatly increased enzyme activity causing drug elimination to be far greater than drug absorption -blood/tissue drug level is too low to be considered effective -MEC cannot be maintained and there is little or no therapeutic effect -processes drug more rapidly -standard dosing may be ineffective
intermediate drug metabolizer
-unbalanced -low enzyme activity -drug elimination is much slower than drug absorption -blood/tissue drug level is too high and toxic effects may occur -MEC is greatly exceeded
poor drug metabolizer
-unbalanced -low enzyme activity -drug elimination is slower than drug absorption -blood/tissue drug levels are too high and toxic effects may occur -MEX is greatly exceeded -standard dosing is too high -processes drug more slowly than expected
what is considered a pre-mutation in fragile X
-under 200 repeats
incidence of multi cystic renal dysplasia (MRD)
-unilateral and bilateral MRD have an incidence of 1 in 3600 live births
deformation
-unusual forces on normal tissue
what is the application for Hardy-Weinberg equilibrium?
-used to determine carrier frequencies -ex- carrier frequencies of cystic fibrosis in different population groups
tandem mass spectrometry
-used to identify numerous metabolic defects -extremely sensitive to trace metabolites -expensive
CMA technology
-uses binding of probes to asses gains and losses (CNVs) -probes are DNA fragments representing precise chromosomal loci across the genome -probes are arranged on a chip in an orderly way
whole exome sequencing (WES)
-uses similar technology as WGS, but targets only protein-coding regions of DNA that are most likely to have a functional role -these sequencing changes are the cause of many well-known genetic diseases
Autosomal Dominant Inheritance
-usually see disease in every generation -if one parent has the gene, offspring have 50% chance of getting the disease as well -males and females affected equally, male to male transmission occur
non-germline Rb
-usually unilateral
what does VUS stand for?
-variants of unknown significance
allele
-variation in the same gene on homologous chromosomes -an alternative form of a gene -two alleles in an individual occur at the same place on two homologous chromosomes- can be the same or different
is the number of receptor cells constant between each person? what dos a higher number of receptor cells mean?
-vary from person to person -those with higher receptor cells will have greater response to an agonist for those receptors and a lesser response to an antagonist for those receptors
what is morbidity or mortality with neurofibromatosis 2 due to?
-vestibular schwannomas (tumor of tissue that covers nerves) and other cranial spinal tumors
which bleeding disorders are dominant?
-von Willebrand
Vitamin K epoxide reductase complex 1 (VKORC1)
-warfarin's action directed at this -necessary for activating vitamin K clotting factors -variants explain about 15-30% of warfarin dose requirements
codeine
-weak narcotic drug that exerts the most analgesic effect on conversion to morphine -conversion carried out by CYP2D6
nondisjunction
-when a pair of homologous chromosomes may fail to separate from each other in first meiotic division -can result in gamete containing a pair of chromosomes from a single parent rather than a single chromosome homolog
prayer willi syndrome
-when both number 15 chromosomes are maternal with no paternal input
when can genotype frequencies change?
-when individuals from one genotype are more likely to produce offspring with each other than the of other genotypes -when individuals migrate between populations -when reproductively isolated small groups from within or separate from a larger population )genetic drift) -when mutation introduces new alleles -when people with a particular genotype are more likely to produce viable, fertile offspring under a specific environmental condition than individuals with other genotypes (natural selection)
what is the less frequent cause of triploidy?
-when ovum fails to successfully complete meiosis and already has 46 chromosomes and is fertilized by 1 sperm
partial monosomy
-when regions of a chromosome are deleted or duplicated -loss of genetic material may occur from within a chromosome or at the termini
when is pre symptomatic testing done?
-when there is a 100% penetrance rate
multifactorial inheritance and sex
-where a multifactorial condition exhibits a marked difference in incidence with sex, the less frequently affected sex has a higher risk threshold and transmits the condition more often to the more frequently affected sex
symptom of retinoblastoma
-white pupil- leukocoria -can see tumor behind eye
Neurofibromatosis- germ-line mutation
-whole body is affected
when does risk to relatives decline for multifactorial inheritance
-with increasingly remote degrees of relationship
inheritance of G6PD deficiency
-x linked recessive
is Duchene Muscular dystrophy (DMD) dominant or recessive? what is the incidence? is the penetrance complete or incomplete?
-x linked recessive -1:3600 live MALE births -penetrance complete
inheritance of DMD and BMD
-x-linked recessive
inheritance of G6PD deficiency
-x-linked recessive -genotype/phenotype correlation is not perfect
manifestations of heterozygous familial hypercholesterolemia
-xanthomas of the tendons around knees and elbows; incidence increases with age and manifests in 80% -coronary disease and infarctions
is chronic myeloid leukemia treatable?
-yes
is genetic testing available for TPMT deficiency?
-yes
is genetic testing for trimodal activity available (TPMT)
-yes
is there always a family component for hunting tons?
-yes -always lethal
are genetic tests done for thiopurine methyltransferase (TPMT) and the meds that it metabolizes? why?
-yes -because if you are a low metabolizer, they can become toxic very quickly and can be fatal
are epigenetics reversible? can they be transmitted?
-yes -can be stably transmitted from one cell generation to the next in the form of cell memory
are some amino acids coded for by more than one codon? why is this important?
-yes -this redundancy of the genetic code is important because a change in DNA/mRNA sequence does not always result in a change in the amino acid of a protein
can the promoter region mutate? can mutations occur at spliced sites?
-yes -yes
can females exhibit symptoms of hemophilia A?
-yes, depending on X inactivation
can epigenetics be reversed?
-yes, in some cases -people that smoke- causes epigenetic effect that can be reversed if they quit
what is needed for FISH testing?
-you need to have an idea of what disease you are looking for
posttranslational modification
leads to the formation of 100 or more different amino acid derivatives from the basic 20 -can be permanent or reversible -examples- converting a protein to a functional form, directing a protein to a specific site, aiding in protein secretion, or altering protein activity or stability
