Genetics Exam 1

Familial Alzheimer's Disease

"Early onset" due to sxs starting before age 65 Mutation on chromosomes 1, 14, or 21 - Involved with production of beta-amyloid that clumps together in the brain Account for < 5% of AD cases Autosomal Dominant

Sporadic Alzheimer's Disease

"Late onset" due to sxs starting after age 65 (MC form) Apolipoprotein E (APOE) on chromosome 19 increases risk - 1 (2-3x risk) or 2 (12x risk) copies of the APO e4 gene increase risk of developing AD but does not guarantee it

Phenotypes due to alterations at a single gene are frequently referred to as?

"Mendelian" after Gregor Mendel who showed that some traits were dominant relative to other traits; he called the latter traits recessive

After gender & age, what is the strongest known predictive risk factor for breast cancer? **

+ family Hx

Both BRCA1 & BRCA2 are tumor suppressor genes that normally do what?

Control cell growth & cell death

Incidence of CML

1 to 2 cases per 100,000 in the US -Approx 4,000- 10,000 annually Median age = 55 Risk Factors •Age: Risk increases with age •Males > Females •Exposure to ionizing radiation (MAIN)

Maternal Serum Screening (Prenatal Genetic Screening) **

1. Analysis of various analytes in pregnant woman's blood - Human chorionic gonadotrophin (hCG) - Alpha-fetoprotein (AFP) - PAPP-A - Inhibin - uE3 2. They compare the amount of these analytes to what the average pregnancy produces at a specific gestational age 3. Specific patterns of these analytes are associated with increased risk for aneuploidy & open neural tube defects (ONTDs)

Phases of CML

1. Chronic phase: < 10% blast cells (immature cells), lasts 2-4 yrs 2. Accelerated phase: 10-19% blast cells 3. Final or Blastic phase: >20% blast cells - Blast crisis = >20% blast cells + fatigue, fever, and splenomegaly - Median survival < 4 months at this stage

Sequential/Integrated Screen (Prenatal genetic screening) **

1. Combines 1st trimester screening & 2nd trimester screening 2. Provides risk for Down syndrome, trisomy 18/trisomy 13 & ONTDs These have the highest detection rates of the maternal serum screens Requires 2 blood draws (1st trimester & 2nd trimester)

Noninvasive Prenatal Screening (NIPS) or cell-free DNA (cfDNA): Prenatal genetic screening **

1. Evaluates fragments of DNA in mother's blood that comes from the placenta 2. Provides risk for Down syndrome, trisomy 18, trisomy 13, & sex chromosomes aneuploidy NIPS offers higher detection rates & lower false positives rates than maternal serum screens However NIPS is not diagnostic & does not replace invasive diagnostic testing

Quad Screen (Prenatal genetic screening) **

1. Measures hCG, estriol (uE3), inhibin & AFP 2. Provides risk for Down syndrome, trisomy 18, & ONTDs

First Trimester Screen (FTS) (Prenatal genetic screening) **

1. Measures pregnancy associated plasms protein A(PPAP-A), hCG, & AFP 2. Provides risk for Down Syndrome & a combined risk for trisomy 18/trisomy 13 3. Various factors are taken into consideration: mother's race, age, gestational age, & whether the mother is an insulin-dependent diabetic

First step of Collection: Understand pedigree

1. Recognize, understand, & use standard pedigree symbols

Principles of Teratology

1. Susceptibility to teratogens is variable 2. Susceptibility to teratogens is specific for each developmental stage 3. The mechanism of teratogenesis is specific for each teratogen 4. Teratogenesis is dose dependent 5. Teratogens produce death, growth retardation, malformation, or functional impairment

Combined First Trimester Screen (with U/S) (prenatal genetic screening) **

1. Uses the biochemical portion of the first trimester screen (FTS) & combines it with the first trimester ultrasound (nuchal translucency) 2. Provides risk for Down syndrome & a combined risk for trisomy 18/trisomy 13

Hereditary Colorectal Cancer

2 autosomal dominant, hereditary CRC syndromes have been identified: -Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) -Familial adenomatous polyposis (FAP) An autosomal recessive CRC syndrome, MUTYH-associated polyposis (MAP), is a variant of FAP and also a hereditary CRC. Carriers of either Lynch syndrome or FAP have a very high likelihood of developing CRC.

Human genome is estimated to contain how many genes?

20,000 - 25,000 genes

Human development proceeds through how many stages? What are they?

3 stages: pre-embryonic, embryonic, & fetal

What percentage of all successful fertilizations end in miscarriage or spontaneous abortion?

31% 66% of these miscarriages occur before a woman is even aware that she is pregnant

Major Phenotypic Features of CML

50% of pts are asymptomatic upon diagnosis -Increased WBCs (>100,000) on CBC + excess of granulocytes on peripheral blood smear

There are currently how many recognized types of OI, with varying criteria for each including differences in inheritance pattern?

8

TORCH Complex

A collection of infectious organisms including Toxoplasma (T), rubella (R), cytomegalovirus (C), and herpes simplex virus (H); the letter "O" in the acronym represents "others" Clinical & pathological findings in the symptomatic newborn with TORCH complex vary Only a few present with multisystem disease & the entire spectrum of abnormalities Microcephaly, hydrocephalus, & abnormally shaped gyri and sulci are frequently observed

Describe each chromosome

A complex of protein & nucleic acid in which an unbroken double helix of DNA is tightly wound

Characteristics of Autosomal Recessive Inheritance ***

A horizontal pattern is noted in the pedigree, with a single generation being affected. Males & females are affected w/ equal frequency & severity. Inheritance is from both parents, each of whom is a heterozygote (carrier) & each of whom is usually clinically unaffected by his or her carrier status. Each offspring of 2 carriers has a 25% chance of being affected, a 50% chance of being a carrier, & a 25% chance of inheriting neither mutant allele. Thus 2/3 of all clinically unaffected offspring are carriers of the autosomal recessive phenotype. In mating between individuals who mate w/ unaffected individuals who are not carriers have only unaffected offspring. The rare the recessive phenotype, the more likely it is that the parents are consanguineous (related)

Pedigree of Mitochondrial ("maternal") inheritance **

A mitochondrial genetic mutation, indicated by darkened symbols, is passed by the female (circle) to all of her offspring, including males (squares). Among the subsequent offspring, the males do not transmit the mutation, but the females continue to transmit the mutation to all of their offspring because mitochondria are passed through ova, not sperm

Collection example: identifying pt, their 1st, 2nd, & 3rd degree relatives, and info on maternal & paternal relatives

A three-generation family typically begins with the pt's generation & includes the parents & grandparents. If the pt and/or his or her siblings have children, the pedigree may be extended to include a 4th generation. asking about pt's maternal & paternal relatives is the basic structure of his/her family

Characteristics of Autosomal Dominant Inheritance**

A vertical pattern is observed in the pedigree, with multiple generations being affected. Heterozygotes for the mutant allele show an abnormal phenotype. Males & females are affected with equal frequency & severity. Only 1 parent must be affected for an offspring to be at risk for developing the phenotype. When an affected person mates w/ an unaffected one, each offspring has a 50% chance of inheriting the affected phenotype regardless of sex of the affected parent- specifically, male-to-male transmission occurs. The frequency of sporadic cases is positively associated with the severity of the phenotype. Autosomal dominant phenotypes are often age dependent, less severe than autosomal recessive phenotypes, & associated with malformations or other physical features.

Diagnostic Testing for Alzheimer's Disease

APOE testing not recommended due to inability to detect who will actually develop AD Medical hx, FHX, laboratory testing, mini mental status exam (MMSE) & neuro-imaging should be performed Only definitive dx made on postmortem autopsy with evidence of plaques & tangles in the brain

What type of medications have been used to tx pts with mild-moderate AD?

Acetylcholinesterase inhibitors

Tx of Alzheimer's Disease

Acetylcholinesterase inhibitors -Used to tx mild-moderate AD -Increase amount of acetylcholine by blocking destruction Ex: Donepezil, Galantamine, Rivastigmine N-methyl-D-aspartase (NMDA) receptor antagonist -Used to tx moderate-severe AD -Decreases amount of glutamate which is thought to contribute to nerve degeneration -Can combine with acetylcholinesterase inhibitors Ex: Memantine

Types of Leukemia (4 major)

Acute -Acute lymphocytic leukemia (ALL) -Acute myelogenous leukemia (AML) Chronic -Chronic lymphocytic leukemia (CLL) -Chronic myelogenous leukemia (CML) - Associated with Philadelphia chromosome

Oculopharyngeal MD

Adulthood onset, between 40-70 years. Eyelids, throat, and face muscles are affected first. As the disease progresses the shoulder and pelvis become involved.

age 35 or older at time of delivery

Advanced Maternal age

Screening Methods for Osteogenesis Imperfecta

After the collagen mutation has been identified, additional family members may be screened using PCR technique. Ultrasound exam performed in a center with experience in diagnosing OI can be valuable in the prenatal diagnosis of the lethal form and most severe forms prior to 20 weeks' gestation; milder forms may be detected later in pregnancy if fractures or deformities occur. -Prenatal testing in at-risk pregnancies may also be performed through the use of molecular genetic testing.

Why is 35 or older considered advanced maternal age?

Age 35 was chosen as the cutoff because the chance that woman will have a fetus with Down Syndrome at this age is approximately 1 in 200, & this is used to be the risk for miscarriage from amniocentesis. Therefore, it was thought that an invasive diagnostic test should be offered to women who were at least as likely to have an affected pregnancy as to have an adverse outcome form the procedure itself

Describe Information gathering: Component of clinical genetic counseling sessions

All genetic appointments begin with information gathering The primary data gathering tool of the genetic counselor is the FHx, formatted as a pedigree At minimum, creation of the pedigree involves 3 generations, includes all individuals - both healthy & those with health issues - age & sex, ages of diagnosis, treatment of relevant medical/developmental issues, & ages and causes of death. Pregnancies & previous pregnancy losses (miscarriages/stillbirths/terminations of pregnancy) including weeks gestation, are recorded. Ancestry & ethnicity of both sides of the family are ascertained & consanguinity ruled out

Only proven curative therapy for chronic myelogenous leukemia (CML)

Allogeneic bone marrow transplantation

What is the only available curative tx for sickle cell disease?

Allogeneic transplant few pts have a suitable donor available. When a suitable donor is available, stem cell transplant has been reported to produce a disease-free survival rate as high as 85%, with the best outcomes reported in pediatric pts.

MC form of dementia? **

Alzheimer's Disease (AD), 2nd is vascular dementia Commonly affects ages > 60 & results in death w/in 5-10 yrs Lack of communication betwn nerve cells - Loss of cholinergic neurons --> plaques & tangles in brain - Brain atrophy Characterized by memory loss, acalculia (inability to do simple math), lack of visuospatial orientation (why they get lost), confusion Risk factors include increased age, female gender, low education level, & positive family hx •Memory loss, Inability to calculate, Loss of visual-spatial orientation •Usually begins after age 60 •Accounts for 65% of dementia in the US (MC) •Caused by loss of cholinergic neurons in certain brain areas •Formation of beta-amyloid plaques and neurofibrillary tangles in these neurons Familial and environmental factors •Early onset: Symptoms before age 65 (genetic high chance) Mutations on genes 1, 14, or 21 (don't need to know specific genes)

MC form of dementia in older people?

Alzheimer's disease, which involves progressive mental deterioration manifested by memory loss, ability to calculate, loss of visual- spatial orientation, confusion, & disorientation

Amniocentesis (Prenatal Diagnostic testing) **

Amniocytes are removed through the amniotic fluid (transabdominally) for genetic testing Miscarriage risk is dependent on the physician performing the procedure Can test for ONTDs

What is Huntington's disease? Is there a cure?

An autosomal dominant disorder characterized by involuntary movements of all parts of the body, deterioration of cognitive function, & often, severe emotional disturbance There is no cure, and disease progression cannot be halted

Additional Standard Pedigree Symbols: Adoption

An individual adopted into a family has a dashed individual line and the symbol (square or circle) is bracketed. As a general rule, non-biological children, as in the case of adoption, are represented with dashed lines. A child adopted out of a family is represented with a solid line and a bracketed symbol (square or circle). An individual adopted by a relative is connected to the adoptive parent(s) with a dashed line.

When a cell has an extra or missing chromosome

Aneuploidy

One member of a pair of chromosomes is missing from a diploid pair

Aneuploidy: Monosomy

More than 3 copies of a chromsome are present (1 or more extra chromsomes are present w/ a diploid pair)

Aneuploidy: Polysomy

One extra chromosome is present with the diploid pair

Aneuploidy: Trisomy

What does Nondisjunction syndromes include? Types? **

Aneuploidy: a condition in which extra or fewer copies of particular genes or chromosomal regions are present Types: Monosomy Trisomy Polysomy Chromosomal Mutations •Aneuploidy: Embryo has too many or too few chromosomes Monosomy Trisomy (MC 21) Polysomy •Translocation and Inversion: Rearrangement of chromosome arms •Deletions: Part of chromosome is missing (deleted)

What does DNA analysis include ? **

Direct sequencing Polymerase chain reaction (PCR): - can be performed on a very small sample - region of DNA btwn primers is greatly amplified DNA Analysis: Uses Polymerase Chain Reaction (PCR)

HHC caused by?

point mutation in the HFE gene and is inherited in a autosomal recessive pattern Mutations result in increased iron absorption and cause increased iron stores in liver, pancreas, skin and heart

DNA is contained in a double helix in functional units called?

Genes

Congenital Abnormalities **

Approx. 31% of all successful fertilization end in miscarriage or SAB (spontaneous abortion) - 66% of these occur before a woman is aware she is pregnant Between 10-12% of all newborns have some kind of birth defect, ranging from minor biochemical problem to some sort of gross physical deformity Such defects may be caused by a variety of biological, chemical, & physical agents Some contributors to these congenital abnormalities include mutant genes, chromosomal defects, & multifactorial components

What percentage of breast & ovarian cancers are attributable to known predisposing genetic factors? **

Approx. 5-10%

Surveillance guidelines for Sickle Cell Disease

Are individualized depending on the pt's age & disease status

Genetic testing & Counseling for Osteogenesis Imperfecta

As previously stated, mutations in COL1A1, COL1A2, CRTAP, and P3H1 cause osteogenesis imperfecta. These genes are those responsible for coding proteins which assemble type 1 collagen. The importance of type 1 collagen is immense, as it is the most abundant protein in bone, skin and other connective tissues responsible for delivering structure and strength to the entire human body. -When the genes COL1A1 or COL1A2 are altered, it leads to an alteration in the structure of the type 1 collagen molecule. -Mutations in either the CRTAP and P3H1 genes lead to disruption in the normal folding, assembly and secretion of collagen molecules as they together are responsible for processing collagen to its mature form Molecular genetic testing of COL1A1 and COL1A2 detects abnormalities in > 90% of individuals with historically classified OI types I, II, III, IV. -Those individuals who have inherited the disease through mutation have to undergo DNA analysis in order to confirm the diagnosis. This is because these mutations actually code for the N-terminus of the helical region and do not result in the over modified collagen, therefore making it extremely difficult to pick up on gel electrophoresis.

Variants of Familial Adenomatous Polyposis (FAP)

Attenuated FAP -Fewer adenomatous polyps (less than 100.) -Later average onset of polyposis and CRC than classic FAP. Gardener's syndrome -Extracolonic manifestations develop: -Bumps or lumps on the bones of the legs, arms, skull, and jaw; cysts of the skin; teeth that do not erupt when they should; and freckle-like spots on the inside lining of the eyes. MUTYH-associated polyposis (MAP) -Autosomal recessive syndrome resulting from bialleic mutations in the MUTYH gene- results in multiple colorectal adenomas. -Multiple phenotypes: polyposis and nonpolyposis variants -Lifetime CRC risk of approximately 70-75%. -Family history may not be evident.

Phenotypic features of Hereditary Breast & Ovarian CA **

Autosomal dominant pattern of inheritance Early age of breast CA onset (before 50 yrs old) Triple-negative (estrogen, progesterone, & human epidermal growth factor receptor 2 negative) before 60 yrs old Family hx of both breast & ovarian cancer Increased chance of multiple primary cancers, (i.e., bilateral tumors) Increased risk of development of both breast & ovarian cancer in the same individual Family hx of male breast cancer Ashkenazi Jewish ancestry 5-10% of breast cancers are hereditary Lifetime risk of a woman to develop breast cancer is 12% (1 in 8) Besides gender and age, positive FH breast CA strongest predictor Hereditary breast cancer •Early age (<50 years) •Triple-negative breast cancer before or at age 60 •FH of breast AND ovarian CA •Multiple (bilat) tumors •Development of breast AND ovarian cancer in same individual •FH male breast CA •Ashkenazi Jewish ancestry

Familial Adenomatous Polyposis (FAP) **

Autosomal dominant: 50% chance of passing condition to each offspring (even if colon of parent is removed.) Characterized by numerous colorectal adenomatous polyps Classic FAP first develops polyps during teenage years with hundreds to thousands of polyps developing over the lifetime. Nearly 100 % chance of developing CRC from polyps that become malignant by an average age of 45 yo, for carriers of the classic phenotype, without prophylactic tx. Variants: Attenuated FAP, Gardner's syndrome, & MAP

What are the remaining 22 pairs of chromosomes called?

Autosomes

CF: Gastrointestinal Involvement

Meconium ileus affects approx. 20% of newborns with CF. •Caused by the presence of unusually thick fetal waste products (meconium). - Normally broken down by pancreatic enzymes, such as trypsin. In the absence of pancreatic enzyme activity (characteristic of CF), the dense meconium is retained in the fetal intestines.

Hereditary Breast CA Genes **

BRCA1 •Mutation on chromosome 17 •Associated with ovarian CA, female breast CA, prostate CA, & colon CA BRCA2 •Mutation on chromosome 13 •Associated with male breast CA, ovarian CA, prostate CA, & pancreatic CA BRCA1: Lifetime risks •Female breast CA 55-70% •Male breast CA 1% (normal risk is 1 in 833, or 0.12%) •Ovarian CA 40% •Contralateral breast CA 63% BRCA2: •Female breast CA 45-70% •Male breast CA 8% •Ovarian CA 50% •Pancreatic CA 5%

What 2 breast CA genes have been identified as playing roles in hereditary breast & ovarian CA syndrome?

BRCA1 & BRCA2

Describe Information-giving: Component of clinical genetic counseling sessions

Basic information about chromosomes, genes & gene mutations is relayed in language tailored to the individual's understanding, often with the use of diagrams & illustrations to enhance comprehension. Pts are provided with information regarding the genetic condition, including, as appropriate, inheritance patterns & risks of occurrence or reoccurrence. Communication of risk is a particularly challenging aspect of genetic counseling that is complicated both by issues of numeracy & genomic literacy

Characteristic Features Associated with Fetal Alcohol syndrome

Behavior disturbances Brain defects Cardiac defects Spinal defects Craniofacial anomalies - Absent or hypoplastic philtrum - Broad upper lip - Flattened nasal bridge - Hypoplastic upper lip vermilion - Micrognathia - Microphthalmia - Short nose - Short palpebral tissues

Associated Syndromes of Hemophilia: Von Willebrand's disease **

Bleeding disorder associated with low factor VIII activity in which von Willebrand factor (vWF) is missing or does not function properly. Defect in platelet aggregation & adhesion MC inherited bleeding disorder in the US Autosomal Dominant •Von Willebrand disease (types 1 and 2) •Most common congenital bleeding disorder in the US

Dx of CML

Bone marrow bx & aspiration with karyotype - Needed in all cases at diagnosis - Identifies Philadelphia chromosome and other chromosomal abnormalities Fluorescence in situ hybridization (FISH) - Identify bcr/abl rearrangement even if Philadelphia chromosome cannot be identified by cytogenetic analysis Quantitative polymerase chain reaction (PCR) - Baseline measure of bcr/abl transcript levels prior to the start of therapy

Homozygous normal

Both pairs normal

Lifetime risk for a woman to develop breast and ovarian CA **

Breast CA: about 1 in 8 (12%) Ovarian CA: about 1 in 75

Management Options: Breast Cancer Screening **

Breast Examinations •Periodical self exams beginning at age 18 & clinical exams every 6 to 12 months beginning at age 25 for women with the BRCA mutation Mammography •Begin at age 30 or earlier if age of onset of breast cancer in family is less than age 25 MRI •Annually beginning at age 25, 6 months after mammography, in female carriers of BRCA1 or BRCA2 mutation Consistent location for imaging to compare prior studies Current recommendation for both mammography & MRI for breast surveillance, rather than MRI alone BRCA Management: Primary Recommendation: •Bilat mastectomy •Bilat BSO between age 35 - 40, or once child-bearing is complete If patient wants nonsurgical treatment: Strict screening •Self breast exams age 18 •Clinical breast exams q 6-12 months beginning age 25 •MRI breast screening age 25 (more sensitive due to dense breast) •MMG age 30 (earlier if FH breast CA <25yo) •Alternate MRI/MMG q 6 months •Transabdominal U/S and CA-125 (blood test tumor marker) q 6 months starting age 30 •Tamoxifen, esp in BRCA2 (not in males)

Management Options: Male Screening

Breast examinations •Monthly self exams beginning at age 35 and clinical breast exams every 12 months starting at age 35. Mammography •Consider annually for men with gynecomastia or parenchymal/glandular breast density BRCA1 mutation present •Prostate screening starting at age 40 BRCA2 mutation present Consider prostate screening

Associated Syndromes of CF

CFTR-related Congenital Absence of the Vas Deferens (CAVD) •Commonly identified during evaluation for infertility in males without pulmonary or GI manifestations The dx may be established with at least 1 CFTR mutation & any of the following: •Low semen volume •Low sperm count •Absent or malformed vas deferens on PE or imaging Typically produce semen with the following: •Volume of less than 2 mL (normal: 3-5 mL) • pH < 7.0 (normal > 8.0) •Elevated citric acid concentration •Elevated acid phosphatase concentration •Low fructose concentration •Failure to coagulate Clinical evaluation by a urologist is warranted in any of these circumstances, and disease etiology should be determined by molecular genetic testing for CFTR mutations.

What should be offered to all couples who are pregnant or consider pregnancy?

Carrier screening

Communicating Genetic Risk example

Case: 35 yo woman who is 12 wks pregnant undergoes first-trimester screening. Her result is "screen positive," indicating a 1/200 risk for her baby to have Down syndrome Examples of risk communcation: - This is a screening test; it does not mean your baby has Down syndrome -The chance is 1/200, which is one-half of 1%. This means that there is a 99.5% likelihood that your baby does not have Down syndrome - If there were a room full of 200 women your exact age with the same screening result, 1 of them would have a baby with Down Syndrome, but the remaining 199 would not

Genetics of FAP (Familial Adenomatous Polyposis)

Caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene on chromosome 5. -Premature stop codons shorten the APC gene product, which has a role in regulation of cell adhesion and apoptosis. Of pts with classic FAP, approx. 90% have a mutation in the APC gene & 8% in the MUTYH gene. In pts with suspected attenuated FAP, APC mutations are identified in 15% but MUTYH mutations in 25%. While there is often a FHx of polyposis in individuals with FAP, 25% of individuals with APC gene mutations & FAP diagnosis have a de novo mutation.

What are always passed by the female to all of her offspring (including males)?

Characteristics of mitochondrial inheritance patterns Males don't transmit the mutation Females continue to transmit the mutation to all of their offspring because mitochondria are passed through ova (maternal inheritance)

Emery-Dreifuss MD

Characterized by joint contractures that begin in early childhood, and slowly progressive muscle wasting and weakness.

Limb-girdle

Childhood or teenage onset. Shoulder and hip muscle wasting and weakness. May have difficulty dorsiflexing their feet. The lack of movement may cause the patient to trip and fall

Chorionic Villus Sampling (CVS): (Prenatal Diagnostic Testing) **

Chorionic villi cells are removed from the placenta for genetic testing (transabdominally or transcervically) Risk of miscarriage is dependent on the physician performing the procedure 1-2% risk for confined placental mosaicism (cells of placenta do not match the cells of the fetus); if found f/u w/ amniocentesis is recommended to determine if it is confined to placenta or found in fetus as well ONTDs cannot be tested for via CVS. Maternal serum alpha-fetoprotein is recommended to test for ONTDs in pts who get CVS

What are the means by which the genes are transmitted from generation to generation?

Chromosomes

Causes an uncontrolled production of GRANULOCYTIC CELL LINE **

Chronic Myelogenous Leukemia (CML) aka Chronic Myeloid Leukemia Increases amounts of immature & mature granulocytes in peripheral blood & bone marrow Cells produced are morphologically normal BUT may or may not be functional Majority of abnormal cells are NEUTROPHILS Basophilic & eosinophilic cell lines are slightly affected •Chromosomal abnormality: Philadelphia Chromosome •Median age at presentation: 55 years •Exposure to ionizing radiation is only known risk factor Common S&S: •Fatigue, night sweats, fever, unintentional weight loss •Abdominal fullness d/t splenomegaly •Granulocytosis: Overproduction of abnormal granulocytes Treatment: Imatinib mesylate (Gleevec): Inhibits the activity of of the defective gene (the BCR/ABL). Limits the number of blast cells by inducing apoptosis in cells with BCR/ABL.

What types of infections occur in the majority of pts with CF?

Chronic pulmonary infections •Due to the inability of the pulmonary system to mount a defense against pathogens •MC isolated pathogens are Staphylococcus aureus & Pseudomonas aeruginosa. •Concomitant fungal infections with Aspergillus fumigates occur in approximately 10% of CF pts. In the upper airways of persons with CF, nasal polyps, nosebleeds, and chronic sinus infections that are resistant to 1st-line antibiotics are common.

Tobacco

Cigarette smoke contains a number of potential teratogens, including nicotine, cotinine, cyanide, thiocyanate, carbon monoxide, cadmium, lead, & various hydrocarbons There is a direct dose-response reduction in fetal growth Smoking doubles the risk of low birth weight, and increases the risk of a small-for-gestational age newborn by 2.5-fold Smoking also may cause a slightly increased incidence of subfertility, spontaneous abortion, placenta previa & abruption, & preterm delivery

Hemochromatosis: Liver cirrhosis

Cirrhosis, which may be caused by hemochromatosis, is an independent risk factor for the development of hepatocellular carcinoma. While liver bx can be performed to confirm a diagnosis of HH or to diagnose cirrhosis and/or hepatocellular carcinoma, imaging and genetic testing have largely replaced it. Ultrasound is recommended for pats with cirrhosis to evaluate for hepatic cancers. However, MRI is the most sensitive technique.

Clinical Manifestations of Sickle Cell Disease

Clinical manifestations of sickle cell disease are related directly or indirectly to hemolysis & vaso-occlusion. Hemolysis contributes to chronic anemia and subsequent jaundice. Rapid red blood cell destruction increases bilirubin and can lead to cholelithiasis; it also predisposes affected pts to aplastic crisis. Vaso-occlusion can cause tissue ischemia distal to the obstruction and result in tissue death. The brain, lungs, kidneys, and glans penis are frequently affected by this kind of vaso-occlusive disease. Painful swelling of the hands and feet may be the earliest manifestation of sickle cell disease in infants and young children. Acute chest syndrome occurs when vascular occlusion and inflammation affect the small vessels of the bronchial tree. While the S&S of acute chest syndrome vary among pts, infiltrates may or may not be identified on chest x-ray, and pts may present with pain, respiratory illness, fever, and shortness of breath. The leading cause of death among adult pts with sickle cell disease is acute chest syndrome, although infection and fat emboli are also thought to play a role in bringing about this syndrome. An acutely enlarged spleen with a hemoglobin level at least 2 g/dL below baseline are indicative of splenic sequestration of red blood cells. Low platelet count, abdominal pain, nausea, and vomiting may also be present. This presentation occurs most frequently in young children with sickle cell disease and may include a febrile illness. Unlike healthy RBCs that move smoothly through small vessels, sickled RBCs have a shorter half-life (resulting in chronic anemia) When vessels in the brain become occluded, pts with sickle cell disease may present with acute stroke-like sxs such as headache, hemiparesis, seizures, impaired speech, palsies involving cranial nerves, or mental status changes. The age range associated with stroke risk is bimodal—namely, children between the ages of 2 and 9 years and older adults are at greatest risk. In the absence of a stroke, smaller infarctions may lead to gradual cognitive changes in persons with sickle cell disease. Priapism is a frequent occurrence in males with sickle cell disease and may cause permanent tissue damage and impotence if not treated. Other problems associated with reduced blood supply include avascular necrosis of the femoral and/or humeral head, renal failure, cardiomyopathies, delayed growth, and superficial ulcers of the lower extremities. Even though pts with sickle cell trait do not usually have clinical sxs, under some circumstances a change in environmental conditions may lead to episodes of ischemia in these individuals. For example, exposures to high altitudes (such as in mountain hiking or flying in an unpressurized aircraft) and prolonged severe physical exertion can result in sxs similar to those of sickle cell disease due to severe anoxia.

Who are Genetic Counselors? **

Clinicians, trained in the fundamentals of human disease and healthcare, utilizing the most current genetic knowledge and testing to facilitate diagnoses and provide information regarding medical/developmental implications and management. Investigators, deciphering medical & family histories to identify possible genetic etiologies and accessing the most current literature & research to ensure their patients receive the most up-to-date information & options. Educators, transforming complex genetic information & translating it to a form that is understandable & meaningful to patients & audiences of all levels of literacy Counselors, trained in psychological techniques & empathetic communication to help individuals & families adjust to and cope with, the genetic condition or risk in question.

What is currently one of the most widely abused drugs in the US?

Cocaine Most of the adverse outcomes noted in offspring associated with pregnant women's use of cocaine result from the drug's vasoconstrictive & hypertensive effects Placental abruption is the most frequently cited cocaine-related pregnancy complication in cocaine abusers A number of cocaine-related congenital anomalies resulting from vascular disruption have been described, including: -Skull defects, cutis aplasia, porencephaly, subependymal & periventricular cysts, ileal atresia, cardiac anomalies, and visceral infarcts

Occurs when cells lining the colon or rectum become dysplastic & undergo uncontrolled proliferation

Colorectal Cancer (CRC) Polyps: predominantly benign growths that protrude from the mucous membrane into the colon & rectum. -Vary in shape & presentation: i.e.: tubular, flat, indiscreet. -If left untreated: adenomatous polyps may evolve into cancer. 70-80% of CRCs are sporadic w/o any family hx Familial or hereditary patterns need to be recognized early using screening & management guidelines for both pts & relatives. -An individual's lifetime risk of CRC increases approximately 2-fold with a hx of CRC in one first-degree relative. Take a good FHx to assess risk factors: -Many pts with CRC do not experience any sxs until the disease has advanced to the point of tumor growth into the colon lumen or adjacent structures. -A FHx in 1 or more members with CRC or premalignant polyps should be considered significant

Most human diseases results from ?

Combined action of alleles of more than one gene (polygenic)

Gene Testing for breast & ovarian CA

Commercial testing for BRCA1 & BRCA2 gene mutations are available Targeted mutational analysis for pts with relatives that tested positive for deleterious BRCA1 or BRC2 gene mutations 5-10% of women have BRCA1 or 2 gene mutation 4-7% have a harmful mutation in another gene that predisposes to breast and/or ovarian cancer 10-15% of individuals will show a gene mutation of unknown significance

Collection: Comprehensive vs targeted family hx

Comprehensive family history: In a general healthcare setting, providers should collect family histories by eliciting general health info about the relatives represented on a pt's pedigree. Examples of conditions to ask about are: a. Major medical concerns b. Chronic medical conditions (something for which medication or therapy is required, for ex) c. Hospitalizations or major surgeries d. Birth defects e. Mental retardation, learning disabilities, or developmental delay Targeted family history: A targeted family hx is appropriate in a specialized clinical setting or when evaluating a pt for specific concerns. A targeted hx includes info about health problems in a pt's relatives that are related to the condition of concern. When evaluating a pt for a certain syndrome, for example, it would be most beneficial to ask about the presence in other family members of different features associated with that syndrome. A targeted family hx would also be appropriate if the general family hx reveals a possible inherited condition.

A condition in which there is a discrepancy in the genetic makeup between the cells of the placenta & the cells of the fetus

Confined placental mosaicism

When 2 people share a common ancestor

Consanguinity

What is the MC lethal inherited disorder among Caucasians in the US?

Cystic Fibrosis (CF)

A disorder that affects epithelial cells in multiple organ systems **

Cystic Fibrosis (CF) •Pulmonary •Exocrine/Endocrine Pancreas •Intestines •Male genitourinary tract •Hepatobiliary system •Exocrine glands The disease is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Autosomal recessive MC lethal inherited disorder among Caucasians in the US** Affects pulmonary, pancreas, GI, male GU, hepatobiliary, and exocrine systems Causes defective chloride transport across membranes and enhanced sodium absorption Increases water absorption, secretions become thick Presents in early childhood FTT (failure-to-thrive)/poor growth rate •Malabsorption d/t pancreatic insufficiency (floating stools) •Increased caloric expenditure d/t chronic infection Chronic pulmonary infections Pancreatitis (thick secretions from pancreas, can't drain) Biliary cirrhosis Azoospermia - Congenital absence of vas deferens (found later in life)

Involves an ion transport disorder in the epithelial cells of multiple organ systems & results in pulmonary disease, pancreatic dysfunction, hepatobiliary disorders, & exocrine dysfunction.

Cystic fibrosis (CF)

Tx of CML: Tyrosine kinase inhibitors

Imatinib mesylate (Gleevec): targeted molecular therapy - Inhibits the activity of BCR/ABL - Decreases # of blast cells by inducing apoptosis Dastinib or Nilotinib - Used if suboptimal response to Imatinib mesylate (Gleevec)

Genetics & Screening of HNPCC (Lynch syndrome)

Defect in one of several genes that are important in the detection and repair of DNA base-pair mismatches (MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Microsatellite instability: Mutations in one allele of a mismatch repair (MMR) gene results in a characteristic phenotypic DNA abnormality. -Manifested in 95% of cancers in pts with Lynch syndrome by expansion or contraction of DNA microsatellites (short, repeated DNA sequences.) Families should be evaluated first by a genetic counselor and given informed consent before genetic testing is performed. -Genetic screening should be considered for patients meeting the Amsterdam II criteria or any of the revised Bethesda criteria. -Amsterdam II criteria: "3-2-1" rule: 3 affected members - 2 generations - 1 <50 years old. With a documented MMR gene mutation, affected relatives should be screened with colonoscopy q 1-2 yrs beginning at 25 yo or at an age 5-10 yrs younger than the age at dx of the youngest affected family member, whichever is first. Upper endoscopy should be performed q 2 to 3 yrs to screen for gastric cancer due to increased risk in pts with Lynch syndrome. Women should undergo screening for endometrial & ovarian cancer beginning at age 25-35 yrs with pelvic exam, CA-125 assay, endometrial aspiration, & transvaginal ultrasound. -Prophylactic hysterectomy with bilateral salpingo-oophorectomy may be considered, especially in women who are done with childbearing.

Heterozygous Advantage (sickle cell)

Describes the case in which the heterozygote genotype has a higher relative fitness than either the homozygote dominant or homozygote recessive genotype. This specific case of heterozygote advantage due to a single locus is known as over-dominance

Formation of the morula & blastocyst during pre-embryonic development **

Development & Teratogenesis

What type of teratogen was previously used to "support" high-risk pregnancies between 1940-1971 ?

Diethylstilbestrol (DES) Women w/ prenatal exposure to DES had an absolute cancer risk for vaginal clear-cell adencaricoma Researchers have shown that DES produces both structural & function abnormalities The MC reported abnormalities include: - Hypoplastic, T-shaped uterine cavity - Cervical collars - Cervical hood, septa, & coxcombs - "withered" fallopian tubes Affected women are at increased risk for poor pregnancy outcomes related to uterine malformations, decreased endometrial thickness, & reduced uterine perfusion Exposed male fetuses have normal sexual function & fertility, but are at increased risk for epididymal cysts, microphallus, cryptorchidism, testicular hypoplasia, & hypospadias

Advanced maternal & paternal age are associated w/?

Different types of mutations

Typical Analyte Pattern for Down Syndrome, Trisomy 18/Trisomy 13, & Open Neural Tube Defects

Down Syndrome: 1st trimester: hCG is high, PAPP-A & AFP are low 2nd trimester: hCG & inhibin are high, uE3 & AFP are low Trisomy 18 1st trimester: hCG, PAPP-A, & AFP are low 2nd trimester: hCG, inhibin, uE3, & AFP are low Trisomy 13 1st trimester: hCG, PAPP-A, & AFP are low 2nd trimester: hCG, inhibin, uE3, & AFP are NA Open Neural Tube Defects (ONTDs) 1st trimester: hCG, PAPP-A, & AFP are NA 2nd trimester: hCG, inhibin & uE3 are ---, AFP is high

MC type of Muscular dystrophy?

Duchenne Muscular Dystrophy (DMD)

A rod-shaped cytoplasmic protein, & a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane

Dystrophin The dystrophin complex acts as an anchor, connecting each muscle cell's structural framework (cytoskeleton) with the lattice of proteins and other molecules outside the cell (extracellular matrix) Think of it like the glue that holds it together

Clues of Dx of Alzheimer's Disease

Early sxs: short term memory loss plus one or more of the following: - Aphasia (can't understand speech, read/write), apraxia (can't perform everyday movements), agnosia (can't process sensory info ex: using fork as a spoon), or difficulities with executive functioning Personality & behavior changes & hallucinations occur later End-stage disease - Mutism, difficulty eating/swallowing, & incontinence

What are the primary germ layers? What do they mark the beginning of?

Ectoderm, mesoderm, endoderm Their formation marks the beginning of embryonic development. As the embryo develops, these 3 layers give rise to the organs by a process called organogenesis

Dx of Muscular Dystrophies

Enzyme assay examining for elevated creatine kinase (CK) levels is the 1st test to be considered. At the age of 2, these levels are at their highest. Serum tests may demonstrate high levels of myoglobin, which indicates breakdown of skeletal and cardiac muscle tissue. Lung monitoring is a testing method that may determine the functionality of the individual's lung capacity and endurance. A biopsy is the most definitive test to show signs of MD. Genetic testing is the MC method of diagnosing & considered the gold standard.

Process of helping people understand & adapt to the medical, psychological & familial implications of genetic contributions to disease?

Genetic counseling This process integrates: - Interpretation of family & medical histories to assess the chance of disease occurrence or recurrence - Education about inheritance, testing, management, prevention, resources & research - Counseling to promote informed choices & adaptation to the risk or condition

Management & Tx: Hemophilia

Estrogens, oral contraceptives, epinephrine, desmopressin acetate, & vigorous exercise can be used to increase the levels of factors VIII & IX. (male pts primarily) Specific factor deficiencies can be corrected through infusion of synthetic Factors Referral to hemophilia tx centers

If an individual may have inherited a gerline BRCA1 or BRCA2 mutation, will they get breast CA for sure?

Even though an individual may have inherited a germline BRCA1 or BRCA2 mutation, the person may never develop cancer because he or she may never get the second mutation that knocks out the function of the gene and starts the process of tumor formation

Congenital

Evident from birth or before age of 2. It affects both females and males. Some forms progress slowly, whereas others can move quickly and cause significant disability.

Gower's Sign

Evident in most children who suffer from muscular dystrophy Classic sign noted when a child has proximal muscle weakness The child requires use of "walking up" his legs with his hands to maintain an upright posture

What does Cytogenetic Testing do? **

Examines chromosomes to identify structural abnormalities Staining allows for each chromosome to be individually identified The distinct bands of each chromosome revealed by staining allow for analysis of the chromosomal structure Cytogenetic studies: Light microscopy "paints" the chromosomes

Main risk factor for CML

Exposure to ionizing radiation

2 recognized forms of AD

Familial Alzheimer's Disease Sporadic Alzheimer's Disease

15-30% of Colorectal cancers are? **

Familial Colorectal CA Patterns within a family that exist without the identification of a specific mutation are considered familial CRCs. -Result of single-gene mutations, multiple-gene mutations, or combined effect of gene mutations and environmental risk factor. May be due to multiple, non-hereditary causes such as chance alone, shared exposure to a carcinogen in the environment, or similar diet or lifestyle factors. 15-30% of colorectal cancers are hereditary Autosomal dominant •100s of polyps •~100% chance of developing colon cancer (attenuated FAP is 70%) •Colonoscopy beginning age 12; EGD q 1-3 years •Colectomy age 20

What does Diagnostic Testing include?

Family Hx Cytogenic testing: Fluorescence in Situ Hybridization (FISH) DNA Analysis Biochemical Analysis Pedigree Analysis

What is important and should be collected on all couples currently pregnant or considering pregnancy?

Family Hx! Referral for genetic counseling should be offered to any individual or couple who answers yes to one or more of these key FHx questions (in pic)

Prognosis of Muscular dystrophy

Heavily dependent on the type of MD and the rate of progression of the disease. Some types that are slowly progressing may allow for a normal life span, while the more aggressive types cause loss of muscle strength that eventually leads to loss of function, loss of independence, and early death.

Comprises a complex of abnormalities caused by maternal consumption of alcohol & includes growth retardation, CNS dysfunction, & characteristic facial dysmorphology ?

Fetal Alcohol Syndrome Ethyl alcohol (also known simply as alcohol) is one of the most potent teratogens known Because not all children adversely affected by maternal alcohol abuse exhibit the entire spectrum of abnormalities, the term fetal alcohol effect is also used to describe this condition Children with fetal alcohol effect have milder degrees of mental deficiency & emotional disorders; the outcome is more common then the full fetal alcohol syndrome scenario

What is perhaps the MCC of acquired mental retardation?

Fetal alcohol syndrome

Fetal Stage (week 8 through birth)

Fetal development involves ongoing organ development and growth as well as changes in body proportions It begins in the 8th week of pregnancy and ends at parturition (birth) The fetus grows rapidly during this period, increasing in length from approximately 2.5 cm to 35 to 50 cm and increasing in weight from 1 g to 3000 to 4000 g The fetus also becomes more humanlike in physical appearance with each month of gestation The organ development that started during the embryonic stage is completed during the fetal stage.

What is used in prenatal ultrasound? What does it do? **

First Trimester Ultrasound 1. Scan the anatomy: looking for a number of markers from fetal number to placental position 2. As a genetic screen: - Assesses for birth defects & soft markers: soft markers are subtle changes that alter a woman's risk for specific types of aneuploidy: echogenic bowel, intracardiac foci, & shortened long bones - Measures nuchal translucency (NT): Thickening NT can be associated with Down syndrome, cardiac defect, an pending fetal demise. However, it can sometimes be a normal variant 3. To help determine due date Remember, a nml US does not guarantee the birth of a healthy child

Genetic testing for breast & ovarian CA: who should be tested

First test an individual who is affected by cancer before testing unaffected family members If an unaffected family member is then tested for a known mutation, 2 results are possible: POSITIVE: •The individual is at increased risk to develop breast and ovarian cancer NEGATIVE: •The individual is not at increased risk but still has the general population risk •Mutation is not detected due to limitations of test •The individual may have a mutation in a different gene that predisposes the person to breast and/or ovarian cancer

A type of cytogenetic testing that uses a small piece of nucleic acid labeled with fluorescent dye called a probe ? What does it do? **

Flurorescent in Situ Hybridization (FISH) Identifies specific mutated genes (compare the probe to pt DNA) Florescence in Situ Hybridization (FISH) •Uses a probe: A short sequence of nucleic acid matching the gene in question •Labeled with a fluorescent dye •Detects specific sequences on specific chromosomes

Management Options: Ovarian Cancer Screening

For pt with higher, inherited risk of ovarian cancer: •Concurrent transvaginal ultrasound and serum CA-125 levels every 6 months beginning at age 30 or 5 years before the earliest family member was diagnosed with ovarian cancer •These screening techniques have not proven to detect ovarian cancer at an early and potentially more treatable stage •Prophylactic bilateral salpingo-oophorectomy is recommended between the ages of 35 to 40 years or upon completion of childbearing is an effective risk-reduction option

A positive family hx is the strongest known predictive risk factor for breast cancer after?

Gender & age

What kinds of trials are undery way to combat muscular dystrophy?

Gene therapy trials

Testing & Screening for FAP (Familial Adenomatous Polyposis)

Genetic counseling & testing should be offered to pts with 10-20 or more adenomas identified on colonoscopy in their lifetime and to all first-degree relatives of the index case. Commercial APC gene testing is available & is required for a definitive diagnosis of FAP. Germline testing for biallelic germline mutations in the MUTYH gene should be considered in pts with negative APC gene testing to determine a dx of MAP. Children of pts with FAP should undergo genetic screening beginning at age 10 First-degree relatives of affected individuals should undergo yearly colonoscopy beginning at 12 yo if genetic testing cannot be done or is not informative. For classic FAP, complete proctocolectomy or colectomy is recommended, usually before age 20. *almost 100% chance of getting CA from polyps Upper endoscopic evaluation of the stomach, duodenum, and peri-ampullary area should be performed every 1-3 yrs to look for extracolonic adenomas or carcinoma with a diagnosis of FAP, classic or attenuated. Annual thyroid ultrasounds are also recommended. In attenuated FAP, screening is recommended q 1-3 yrs beginning at age 15 If attenuated FAP is suspected, it is important that family members be screened with colonoscopy rather than flexible sigmoidoscopy.

What should be offered to individuals suspected of Lynch syndrome (based on the revised Bethesda criteria or a prediction model) and the first-degree relatives of individuals with a confirmed MMR gene mutation?

Genetic counseling and testing

What is being integrated into virtually every medical subspecialty, with genetic counselors as a part of the healthcare team?

Genetic medicine

Study of biologically inherited traits determined by genes that are transmitted from parents to offspring during the course of reproduction ?

Genetics

Term that described the biologically inherited traits determined by elements of heredity (genes) transmitted from parents to offspring in reproduction

Genetics

Study of the chemical nature of genes & the ways that genes function to affect certain traits

Genomics

The study of all genes in a person as well as the interactions of these genes with one another & with an individual's environment?

Genomics

Difference between germinal mutation and somatic mutation

Germinal mutation occurs DURING formation of an egg or sperm, but if change occurs AFTER conception it is termed a somatic mutation

Other associated Syndromes: Hereditary Diffuse Gastric Syndrome (HDGC)

Germline mutation in CDH1 gene Characterized by highly invasive gastric cancer Lobular breast cancer in women Lifetime risk of breast cancer as high as 60%

Other associated Syndromes: Peutz-Jeghers Syndrome (PJS)

Germline mutation in a tumor suppressor gene STK11 on chromosome 19 Characterized by melanocytic macules (freckles) on the lips, perioral, and buccal regions Multiple gastrointestinal polyps & cancer Absolute risk of breast CA is 55% (mean age of dx is 37 years old) Prevalence of ovarian CA is 21% (diagnosed at an early age)

Other associated Syndromes: Li-Fraumeni syndrome (LFS)

Germline mutation of tumor suppressor gene TP53 on chromosome 17 Can cause Premenopausal breast cancer (usually under 35 yrs old) with: •Childhood sarcoma •Brain tumors •Leukemia •Adrenocortical carcinoma Lifetime risk of breast cancer 50% by 60 yrs old

Chromosome Analysis (karyotype) (testing cells)

Gold standard for diagnosing aneuploidy Provides information on all chromosomes

Carrier Screening

Guidelines recommend that all women be offered screening for cystic fibrosis, spinal muscular atrophy & hemoglobinopathies like sickle cell If there is a FHx of fragile X this should be tested Also ethnic specific, panethnic, & expanded carrier screening is acceptable Downside of the panethnic & expanded carrier screening is that more people will be found to be carriers for at least one condition when tested Residual risk: the risk that an individual is still a carrier for a condition despite a negative screen for that condition If a pt is found to be a carrier for an autosomal recessive condition, the reproductive partner of that pt should be offered carrier testing Couples with consanguinity should be offered genetic counseling to review the increased risks of recessive conditions

common health problems associated with Down Syndrome

Heart defects Intestinal defects Vision problems Hearing loss Infections Memory loss avg life span has increased to ~ 50yo due to recognizing these health conditions

Etiology & Genetics: Hemophilia A **

Hemophilia A "Classic hemophilia"-Mutations of the F8 gene-responsible for making coagulation Factor VIII. Results in production of functionally impaired factor VIII proteins Clinical manifestations proportional to the amount of normal F8 protein present X-linked recessive inheritance (M > W) - intrinsic pathway

Bleeding disorder caused by mutations in the F8 gene, which encodes for factor VIII

Hemophilia A ("classic hemophilia")

Tx: Moderate to Severe Active Bleeding

Hemophilia A - Factor VIII 50 units/kg Hemophilia B - Factor IX 100 - 120 units/kg

Bleeding disorder caused by mutations in the F9 gene, which encodes for factor IX

Hemophilia B ("Christmas disease")

Etiology & Genetics: Hemophilia B **

Hemophilia B -Mutations of the F9 gene-responsible for making coagulation Factor IX. Results in production of functionally impaired factor IX proteins Clinical manifestations proportional to the amount of normal F9 protein present X-linked recessive inheritance (M >W) intrinsic pathway Similar to Hemophilia A

Collection example: Ancestries added to pedigree finished

Here is the finished pedigree, which includes the info collected at each step of the process. To the untrained eye, it may look cluttered. However, once you understand the symbols and notations, you can see that a pedigree is a great way to keep a lot of information organized and easily accessible. With family hx displayed in this format, you can also easily visualize inheritance patterns or clustering that may make interpretation easier.

Genetics of Hemochromatosis **

Hereditary disease with mutation in the HFE gene causing an increase in the intestinal absorption of iron and this results in increase iron deposits in body tissue Autosomal recessive disorder MC single-gene disorder among Caucasians in the US Caused by increased absorption of iron "iron elephant" Presents age 40 or older •Fatigue •Abnormal LFTs •Diabetes •Arthralgias (MCPs) •Hyperpigmentation (less common) Sex-influenced phenotype: HH lower incidence in females d/t blood loss with menstruation Diagnosis: •Elevated transferrin saturation •Elevated serum ferritin •Serum iron and TIBC may be increased Management: Therapeutic phlebotomy is tx of choice

Progressive, irreversible disease characterized by involuntary movements, loss of cognitive function, & emotional disturbances **

Huntington's Disease AKA Huntington's chorea Autosomal dominant Deposits of amyloid-related protein in basal ganglia Onset of sxs to death usually spans 15 yrs Fatal, progressive disease •Characterized by involuntary movements: Huntington's Chorea •Deterioration of cognitive function •Emotional disturbances Autosomal dominant •Affects people of N European ancestry •HD gene on chromosome 4 (don't memorize) •Heterozygotes just as affected as homozygotes Onset of symptoms usually between 30—50 years of age

What improves overall survival and reduces symptoms of sickle cell anemia?

Hydroxyurea

What has been the MC prescribed therapy for sickle cell disease? What does it do?

Hydroxyurea Reduces the frequency of painful episodes by 50% Works by multiple mechanisms. -Improves red blood cell survival by inducing production of fetal hemoglobin (HgF) that is resistant to sickling. -Lowers the white blood cell count and arrests inflammatory processes. -Acts as a vasodilator to help improve blood flow and reduce the risk of stroke.

Sickle cell trait is usually clinically silent but it may produce sxs when exacerbated by?

Hypoxia

2nd step of Collection: Produce at least a 3-generation pedigree

Identification of the pt

Note on prenatal testing

If a mother has had a first trimester screen, noninvasive prenatal screening, or the diagnostic chorionic villus sampling, maternal serum alpha-fetoprotein can be drawn to provide a risk for ONTDs only. The quad screen should not be ordered if any of these test have been done previously.

Hopeful Benefits due to the applications of the Human Genome Project

Improved disease diagnosis Improved ability to detect genetic predispositions to disease Development of drugs based on molecular info Use of gene therapy & control systems as drugs Creation of "custom drugs" based on individual genetic profiles

When is CF MC diagnosed?

In early childhood, usually during the 1st year of life: Failure to thrive & poor growth rate is a common finding in children. •Malabsorption associated with pancreatic insufficiency •Increased caloric expenditure 2ndary to chronic infection (body has to spend more energy fighting off infection) CF may initially be misdiagnosed as celiac disease, pancreatitis, asthma, or chronic bronchitis, due to the constellation of sxs.

Inversion mutation example

Inversion by reversal of the region between 2 chromosomal break points Phenotype effect can be very small or very large

Diagnostic Testing for Huntington's Disease

Medical & family hx CT scan shows cerebral and caudate nucleus atrophy MRI & PET show decreased uptake in an anatomically normal caudate nucleus Genetic counseling & testing should be offered to children of affected parents

Pathophys/Phenotypic Feature of CF

In the lower airways of CF pts, thick mucus production and neutrophilic inflammation build up to cause airway obstruction. •Chronic cough w/ or w/o sputum production •Dyspnea on exertion Eventually, structural changes take place in the airway (remodeling) & cause chronic bronchitis. Functional lung parenchyma is replaced with nonfunctional tissues, such as cysts, abscesses, & fibrosis. •This leads to increased alveolar resistance & causes high BP in the pulmonary artery & R side of the heart --> cor pulmonale The chronic inflammation, structural changes, & increased pressure associated with this disease all contribute to damage in the vascular beds. •Hemoptysis (coughing up blood) is a common presenting feature of CF during periods of acute infection. Chronic blood loss or multiple episodes of massive hemoptysis can result in iron-deficiency anemia in these pts Pts who retain mucus, especially in the upper lobes, may show hyperinflation on chest x-ray.

What is the Incidence of Hemochromatosis?

Incidence of 1 in 200 Caucasians in the U.S. Males manifest more sxs than females due to menstruation

Other associated Syndromes: PTEN Hamartoma Tumor Syndrome (PHTS)

Includes Cowden Syndrome & Bannayan-Riley-Ruvalcaba Syndrome with Cowden Syndrome: -Germline mutations phosphatase and PTEN tumor suppressor gene on chromosome 10 -Multiple hamartomas, trichilemmomas, oral fibromas, punctate palmoplantar keratoses -Excess of breast CA & benign breast disorders -Gastrointestinal, endometrial, colorectal, and kidney cancer -Benign and malignant thyroid disease -Lifetime risk of breast cancer 25-50% in women

Management, Tx, and Surveillance of CF

Increased overall survival & enhanced QoL can be best achieved when a comprehensive tx plan is developed early on. Attention focused on treating disease manifestations & preventing future complications. •Replacement of pancreatic enzymes & deficient vitamins •Bronchodilators to maintain patent airways •Antibiotics for respiratory infections(can't clear mucus) •Administration of mucus-thinning agents •Pain management & anti-inflammatory agents •Chest physiotherapy Collectively, these txs optimize pulmonary function Immunizations for common pulmonary pathogens are recommended as preventative measures, including , pertussis, measles, varicella, Haemophilus influenzae type B, Streptococcus pneumonia, respiratory syncytial virus (RSV), and influenza virus. Regularly scheduled PEs are important components of pulmonary surveillance. •Pulmonary function testing •Chest x-rays •Sputum cultures All respiratory irritants—such as smoke, dust, and fumes—should be strictly avoided. Gastrointestinal complications require nutritional support & enzyme replacement therapy. •Pancreatic enzyme & fat-soluble vitamin supplementation (ADEK) are mainstays of prevention. (may have blood clotting issues due to lack of Vit K) •Pts with a low BMI may benefit from increased caloric intake & use of high-fat supplements under the supervision of a nutritionist specializing in CF. Annual screening of blood glucose levels for CF-related diabetes should be performed •If present, this disease (DM) should be managed by an endocrinologist. Biliary cirrhosis should be suspected when hepatic enzymes are elevated. •Obstruction of the bile duct can be managed through use of oral bile acids, which dissolve and prevent gallstones. Baseline bone density should be determined in adolescence or as early as possible and repeated annually to detect evolving osteoporosis. Maintaining overall hydration status is also important. •Decreased total body water can exacerbate thickening of secretions and associated complications. Regular physical exercise has also been shown to improve bone health and patency of airways. There is no cure for CF at present. Delaying respiratory tract infections and earlier lung transplantation are the most promising therapies. The improved survival of women with CF is responsible for an increase in the pregnancy rates among these pts •Women with CF should receive prenatal counseling, & should be managed by a team of professionals including a CF specialist, a dietician, & a high-risk obstetrician.

Phenotypes due to alteration at a single gene are characterized as?

Mendelian Monogenic human disease are frequently referred to as Mendelian disorders

Components of clinical genetic counseling sessions: Psychosocial & support

Individuals experience a myriad of feelings when a genetic diagnosis is made Genetic counselors are trained in the technique of providing anticipatory guidance, helping families to come to terms with and gain some sense of control over, the genetic situation by understanding what to expect from a physical, developmental and emotional perspective •Example: Anticipating heightened feelings of grief or loss on the anniversary of a child's or loved one's death Genetic counselors are trained to assess & recognize psychosocial challenges that may warrant referral to a mental health professional

When does CF typically present?

Infancy & early childhood

Collection of a pt's family hx, in conjunction with his or her traditional medical hx info can?

Inform dx: Whether a pt presents with a relatively uncommon single-gene disorder such as hemophilia, or a common complex condition such as cancer, knowledge of family hx can promote more rapid dx, streamlined testing, and better long-term management. Promote risk assessment: Medical family hx information, in combo with other risk factors, can be used to estimate a pt's risk of developing the same or similar condition as a relative, and to stratify that risk into higher or lower categories. Info such as the # of affected & unaffected relatives, age at onset of disease, severity of disease, & degree of relationship come into play in this assessment. This assessment can also determine if a pt is an appropriate candidate for genetic testing & can identify other relatives who might also be at high risk to develop a medical condition. Prevent, detect, and manage disease: Once a pt's risk has been determined, the provider can suggest or advise appropriate interventions to improve the pt's overall health & possibly prevent the onset of disease. In addition, if family hx reveals that a pt is at increased risk, the provider can implement screening strategies to detect disease early, when it is most treatable. Some pts at increased risk may already have begun to manifest disease. For those individuals, family hx assessment may help providers identify & manage the illness. The emphasis on disease prevention & management based on the family hx may also motivate a change in behavior that forestall disease or reduce its adverse affects. Build rapport with patients: The act of taking a family hx is an excellent opportunity to build a relationship with the patient. Through this interaction, the healthcare provider may also become aware of the pt's motivations and concerns, as well as family dynamics. All such info can be beneficial as the provider helps the pt make health-related decisions.

What are the components of Clinical genetic counseling sessions ? **

Information gathering Risk assessment Information-giving All genetic counseling sessions begin with information gathering •Pedigree constructed from information gathered •Risk assessment: Determined based on pedigree (different patterns)

What does genetic counseling involve?

Information gathering in the form of health & FHx Risk assessment to determine the likelihood of genetic disease, common disease risk & recurrence risk Ascertainment of appropriateness of genetic testing, which tests to consider & which laboratory to use Interpretation of genetic test results in the context of medical & FHx Information giving regarding disease manifestations, risks, management recommendations & implications of test results for family members Provision of psychosocial counseling and support.

Inheritance & Incidence of Cystic Fibrosis (CF)

Inheritance of CF follows an autosomal recessive pattern. •2 copies of the mutated gene are required to cause disease. •The risk of inheriting the CFTR mutation in 2 alleles & developing the disease is 25% if both parents are carriers. CF is the MC lethal inherited disorder among Caucasians in the US. •MC in Northern European descent •Disease incidence is 1 in 3200 live births •Approx. 1 in 25 is a carrier

Course of CML

Insidious onset with slow progression Initially, the patient may be asymptomatic As the tumor burden of abnormal cells increases, the amount of resources for healthy, functioning cells (WBCs, RBCs, and platelets) decreases -As a result there is a decreased # of healthy cells→ BLAST crisis similar to acute leukemia presenting ill with infections, anemia, and bleeding episodes

What is essential to ensure appropriate application of genomic medicine advances?

Interprofessional education & collaboration between genetic counselors & other healthcare providers

What is effective for tx of cystic acne but is also considered to be one of the most potent teratogens in widespread use ?

Isotretinoin

Assess to genetic counselors

It is recognized by the genetic counseling community that access to genetic counselors is limited by numbers & geography It is unlikely there will be enough genetic counselors to meet the expanding need Several companies providing telegenetic services have sprung up in recent years, & clinics and hospitals are utilizing these technologies to reach pts who live in more remote or rural areas. Video education is also being used to provide basic educational content, allowing the counselor to serve more pts by focusing on their individual needs.

Dx of Hemochromatosis

Laboratory studies include -Serum iron- normal to increased -Serum ferritin- increased -TIBC- normal to decreased -Serum transferrin saturation- increased Elevated transferrin saturation levels are typically the earliest phenotypic manifestation of HH, preceding clinical manifestations of the disease.

Cancer that starts in blood cells that are produced in the bone marrow causing increased number of immature blood cells

Leukemia

Cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of blood cells to be produced and enter the bloodstream

Leukemia

Genetics & Leukemia

Leukemia has been thought to be sporadic Several genes have been identified since 2008 linked to hereditary leukemia We'll focus on CML

A word of caution regarding NIPS

Many pt's have a misunderstanding of the limitations of NIPS & do not realize that the possibility of a false positive as well as a false negative exists. It is important to remind your pts of these limitations. For ex: a pt with a low risk of NIPS who presents with ultrasound findings suggestive of trisomy 13 during the anatomy scan should still be offered amniocentesis despite the low-risk NIPS result

MCC of inherited CRC & responsible for 3-5% of colonic adenocarcinomas? **

Lynch Syndrome (HNPCC), formerly called hereditary non-polyposis colorectal cancer (HNPCC) Highly penetrant autosomal dominant- gene mutation carriers have 70-75% lifetime risk of developing CRC. Predominantly affects right side of colon.(sporadic more left side) May develop few to no polyps; rapid transformation from normal tissue to larger, flatter adenomas to cancer in about 35 months (as opposed to a 10 year transformation in sporadic cancer.) Occurs at a younger age than sporadic CRC (mean age is 48 yo.) Other cancers may arise in these families including: -Endometrial, stomach, ovarian, pancreatic, urinary tract, small bowel, biliary tract and brain cancer Amsterdam Criteria II •3 or more relatives with CRC, small bowel, ureteral, renal, or endometrial CA (GI or reproductive tract) •One should be 1st degree relative of the other two •2 successive generations affected •1 family member dx < age 50 •FAP excluded •Verified by pathologic examination Screening •Colonoscopy q 1-2 years starting age 25 •EGD q 2-3 years •Endometrial screening: U/S, EMB (endometrial biopsy), CA-125

What genetic causes of two autosomal dominant, hereditary colorectal cancer syndromes have been identified?

Lynch syndrome (HNPCC) & familial adenomatous polyposis (FAP)

Myotonic (Steinert's Disease)

MC adult-onset form. The facial and neck muscles are often affected first. Sxs include cataracts, sleepiness and arrhythmia. A unique characteristic is difficulty relaxing a group of muscles once it has contracted.

Duchenne MD

MC form of muscular dystrophies Sxs begin in childhood, before age 3. Most are wheelchair bound by age 12 and die of respiratory failure in their early to mid-20s It is MC among males

Management & Tx of Muscular Dystrophies

MD is a progressive disease, and there is no cure or specific tx to reverse its progression. Tx mainstays are meds & physical therapy. The 2 MC meds are corticosteroids & cardiac meds. Although there is no cure for MD, genetic research is exploring gene therapy.

Diagnosis of sickle cell disease?

Made from hemoglobin electrophoresis and other confirmatory testing after a positive screening test

Indications for Cytogenetic Analysis

Malformations associated with particular syndrome or aberration Serious mental or physical developmental problems Maldefined genitalia (internal or external) Primary amenorrhea or delayed pubertal development Males with learning or behavioral disorders who are taller than expected Malignant or premalignant disease Parents of a pt with a chromosome translocation Parents of a pt w/ a suspected syndrome Couples with a hx of multiple spontaneous abortions of unknown cause Infertility not caused by obstretic or urogential problems Prenatal diagnosis

Management Options: BRCA gene mutation present with a personal history of breast cancer

Management includes reducing risk of a new primary breast CA in the ipsilateral breast as well as an increased risk of a new contralateral breast CA: -Ipsilateral mastectomy, contralateral prophylactic mastectomy, & prophylactic bilateral salpingo-oophorectomy in premenopausal pts -Adjuvant therapy with Tamoxifen or an aromatase inhibitor to decrease risk of contralateral breast CA -Prophylactic bilateral mastectomies is NOT recommended in pts with ovarian cancer with BRCA gene mutation due to high mortality rate at 5 yrs post-diagnosis (recommended mastectomies at least 5 years after diagnosis)

Management Options: BRCA gene mutation present with no personal hx of breast cancer

Management includes reducing risk of breast & ovarian cancer: -Bilateral salpingo-oophorectomy between the ages of 35 & 40, or once childbearing is complete -Intensive breast cancer screening -Consider hormonal & surgical risk reduction, such as bilateral mastectomy -Men, screening for breast & prostate cancer

Management and tx: Sickle Cell Disease

Management of sickle cell disease primarily focuses on prevention of crises and management of sxs. Pts should be counseled to avoid precipitating activities that might lead to sickle cell crisis, such as dehydration, physical stress, infection, change in altitude, and prolonged exposure to extreme temperatures of heat or cold. Sxs associated with crises are addressed specifically, and a pain management plan should be developed for this possibility, which may involve the use of opiates and other analgesics. Broad-spectrum antibiotics are indicated when the pt presents with fever. It is important that affected individuals stay current on immunizations (i.e., influenza, pneumonia). Furthermore, pts should be counseled to seek immediate medical attention for signs and sxs of crises so as to prevent complications. Surveillance is individualized, but laboratory tests routinely include annual CBC, reticulocyte count, iron status, liver enzymes, bilirubin, blood urea nitrogen, creatinine, and urinalysis. Doppler studies of the brain to detect areas of decreased or increased flow, chest x-rays, pulmonary function testing, gallbladder ultrasound, and echocardiogram may be indicated depending on the pt's status and age. Red cell transfusions of sickle negative and leukoreduced blood by simple or exchange transfusion can benefit pts in those indicated by decreasing their risk of stroke or recurrent CVA, pulmonary hypertension, and painful crises. Conversely, repeated transfusions will result in iron overload, so iron and ferritin levels must be monitored closely and reduced before iron accumulates and causes permanent organ damage. Repeated or prolonged transfusion regimens can also result in alloimmunization, or the exposure to foreign antigens in the red blood cell unit. This condition results in circulating antibodies in the patient, making it more difficult to ensure future compatibility with donor red blood cell units.

Associated Syndromes of Muscular dystrophies

Many inheritable diseases affect the muscles, the nerves, or the neuromuscular junction. The difference is that other diseases do not have the same genetic defects that are found in the group of MD diseases. The differential diagnosis should include diseases such as congenital myopathy, spinal muscular atrophy, and congenital myasthenic syndromes.

Each gene contains regulatory elements that control when that gene is active in producing what?

Messenger ribonucleic acid (mRNA) (transcription)

Facioscapulohumeral (FSHD)

Most commonly seen during the teenage years, onset can be almost any age. Initially noted in the face and shoulders. Often have difficulty keeping their eyes closed while sleeping. Scapular winging can be noted.

Group of genetically inherited noninflammatory diseases that are characterized by progressive muscle wasting or atrophy **

Muscular Dystrophies Caused by a gene mutation that affects the production of muscle proteins needed to build healthy muscle tissue Absence of dystrophin in Duchenne Muscular Dystrophy (DMD) causes the muscle tissue to lack integrity. Muscular dystrophies affect skeletal muscles primarily in males The 2 MC types are Duchenne Muscular Dystrophy (DMD) & Becker Muscular Dystrophy (BMD). X-linked recessive: Mother carries the affected gene and passes it to her son •Each son has a 50% chance of acquiring DMD •Each daughter has a 50% chance of becoming a carrier Absence of dystrophin causes the muscle to lack integrity Pseudohypertrophy Gower's sign DMD: onset early childhood, wheelchair by 12, lifespan 20s BMD: Later onset, lifespan 40s

Collection of muscle-wasting conditions?

Muscular dystrophy

What is a change in DNA that may adversely affect the host? What are the types? **

Mutation Types: Germinal mutations Somatic mutation Chromosomal abherrations Mutation •Alleles become heterozygous •Inherited or spontaneous •Chromosomal

Congenital absence of the vas deferens is a disorder related to?

Mutation in the CFTR gene

Other associated Syndromes: Lynch Syndrome/ Hereditary nonpolyposis colon cancer (HNPCC) **

Mutations in mismatch repair genes (MSH2, MLH1, MSH6, and PMS2) & mutation of epithelial cell adhesion molecule (EPCAM) gene Primary cancers of the colon, endometrium, ovaries, and stomach MSH2 & MLH1 gene mutations have a lifetime risk of ovarian cancer of 4-12%

Founder Effect **

Mutations specific to a family or common ancestor •Ashkenazi Jewish heritage & families originating from the Netherlands, Iceland, Sweden, Italy, France, South Africa, Pakistan, Asia, French Canadians, Hispanic, and African Americans Also accumulation of random genetic changes in an isolated population as a result of its proliferation from only a few of its few apparent colonizers Reoccur generation after generation "Ethnic Specific" mutation genetic testing panels available (ex: Ashkenazi Jew specific) General population: •1 in 400 to 800 has BRCA1 or BRCA2 mutation Ashkenazi individuals: •1 in 40 has BRCA1 or BRCA2 mutation The accumulation of random genetic changes in an isolated population as a result of it's proliferation from only a few parent colonizers •Occurs when a small group of migrants that is not genetically representative of the population from which they came establish in a new area •Example: Ashkenazi Jews carry higher incidence of BRCA mutations

Myeloproliferative disorder (overproduction) of the granulocytic cell line in the bone marrow is either ACUTE or CHRONIC

Myelogenous leukemia Chronic myelogenous leukemia (CML) is usually insidious in onset, progressing over many months to yrs Acute myelogenous leukemia (AML) is usually rapid in onset

Is there a cure for muscular dystrophy?

NO, currently there is no cure

Factors that are found to slow progression of Alzheimer's Disease

NSAIDs Statins (HMG-CoA reductase inhibitors) Ethanol intake (moderate) Social support

Presentation of Hemochromatosis

Nicknamed "the Iron Elephant" Affected individuals typically present in their 40's. Iron accumulation over time leads to liver cirrhosis and other organ failure. Asymptomatic disease is common. Males are more likely to present than females due to regular blood loss during menstruation (referred to as sex-influenced phenotype). Typically present with non- specific complaints such as abdominal pain, arthralgia, and fatigue. Other findings may include abnormal liver function tests, diabetes, and hyperpigmentation of the skin. Less common findings include hepatomegaly, heart murmurs, conduction disturbance on EKG, hypothyroidism, hypogonadism, and arthritis.

Do screening methods provide a prenatal diagnosis of aneuploidy?

No

Tx of Huntington's Disease (HD)

No cure & progression cannot be halted Symptomatic tx - Drugs that block dopamine receptors may control dyskinesia & behavioral disturbances •Phenothiazines, Haloperidol •SE: sedation, rigidity/stiffness in some cases - Speech therapy - Physical therapy - Occupational therapy

Management & Tx of Osteogenesis Imperfecta

No tx exist Management of the disease includes: -multidisciplinary team of orthopedics, physical therapy, pediatric dentistry and otology/otolaryngology -Brace the limbs, orthotics to provide stabilization, promotion of physical activity in the appropriate environment including physical and occupational therapy to maximize bone stability, improve mobility, prevent deformities and contractures -Tx of fxs will be most substantial with intramedullary rodding prn, casting along with short period immobility and supplementation with physical therapy as soon as the casts are removed -In those with DI (dentinogenesis imperfecta), dental care is aimed to maintain permanent dentition with optimal gingival health and dental appearance with twice yearly visits.

Failure of chromosome to separate (disjoin) & move to opposite poles of the division spindle ?

Nondisjunction

Etiology of Sickle Cell Disease

Normal adult hemoglobin is designated hemoglobin A (HbA), whereas adult sickle hemoglobin is designated as hemoglobin S (HbS). Hemoglobin S is correlated with lower rates of mortality among carriers who are of African and Mediterranean descent, because the HbS allele decreases the risk of infection by malarial parasites endemic in those areas. This property is referred to as heterozygote advantage.

How many chromosomes do humans usually have? Pairs? **

Normally: 46 Pairs: 23 One of these pairs, consisting of the sex chromosomes X & Y, determines the sex of the individual females have the pair: XX males have the pair: XY Chromosomes •23 pairs, including XY •Locus: Exact location of a gene •Alleles: Homologous copies of a gene

Note on Prenatal testing Laboratories

Note that many laboratories offer these various prenatal screens. The purpose of the descriptions in this chapter is to summarize the various products currently on the marker; it is recommended that you check with the laboratory you are using for specifics

Occurrence rates of Osteogenesis Imperfecta

OI has an incidence rate of 6-7 people per 100,000 persons worldwide with Type I & Type IV noted to be the MC forms with an incidence rate of 4-5 per 100,000 persons. Type II has a reported incidence rate of 1 in 60,000 at birth. (most severe) Very few cases of Type V, VI and VII have been reported.

Inheritance patterns of Osteogenesis Imperfecta

OI is now known to have different inheritance patterns: -Autosomal dominant inheritance: Types I-V -Autosomal recessive inheritance: Types VII-VIII -Sporadic mutations are present in the more lethal forms of OI as well, occurring in the germ-line in one of the parents.

CF: Hepatobiliary Disease

Obstruction of the biliary tract due to thickened mucus •Leads to congestion of the liver --> biliary cirrhosis •As damage to the liver progresses, the pt may experience portal hypertension & develop varices (veins through neck when liver cannot handle inflow of venous blood through the portal blood system. It will find ways around the liver, one way is through veins around neck, swelling of neck --> varcies) Liver disease is the 2nd-leading cause of mortality (after pulmonary disease) in pts with CF.

Karyotype of Down Syndrome (Trisomy 21) **

Often related to advanced maternal age 21 has extra chromosome Distinguishing characteristics: - short neck with a excess skin at back of neck - flattened facial profile & nose - relatively small head, ears & mouth - upward slanting eyes with a palpebral fissure on inner corner of eye - wide short hands with short fingers Trisomy 21: Down syndrome •Intellectual disability •Characteristic facial features •Heart defects (nearly 50%) •Vision/hearing problems

Heterozygous translocation

One pair Interchanged, one pair normal

Human development is divided into three stages: pre-embryonic, embryonic, and fetal **

Organogenesis occurs during the embryonic stage. Each bar indicates when an organ system develops. The dark-shaded area indicates the periods most sensitive to teratogenic agents. (3 & 16 wks is critical period for teratogenic effects) Most damaging during primordial organ system formation

Disorder characterized by collagen type I malformation leading to bone instability

Osteogenesis Imperfecta

Results from a mutation in the genes for proteins that code for collagen type I **

Osteogenesis imperfecta (OI) This leads to the weakening of connective tissue, especially bones. -Mutations in the COL1A1, COL1A2, CRTAP, and P3H1 genes cause osteogenesis imperfecta with COL1A1 and COL1A2 responsible for > 90% of cases. -The weakened bones often fracture, MC in the extremities, which is why this disease is frequently referred to as "brittle bone disease" Eight types •Types I, II, III, IV, and V are autosomal dominant Defect in coding of proteins for collagen type I Phenotypic features •Predisposed to fractures •Short stature •Dentinogenesis imperfecta •Codfish vertebrae •Rhizomelia •Coxa mara •Blue sclera

Types of Teratogens **

Pharmacological: - Thalidomide - Diethylstilbestrol (DES) - Retinoic acid Infectious agents: - Toxoplasma gondii - Rubella - Cytomegalovirus (CMV) - Herpes - Congential syphillis - Zika virus Industrial agents: - Lead - Mecury - Pesticides/herbicides Recreational: - Alcohol - Tobacco - Cocaine Drugs: Blood pressure, antifungals, alcohol, hormones, retinoids TORCH: Infections (toxoplasma, other, rubella, CMV, HSV) Fetal Alcohol Syndrome: Spectrum of features Tobacco: low birth weight Cocaine: Vasoconstrictor and hypertensive - Placental abruption Griseofulvin - Antifungal teratogenic

Translation ultimately determines?

Phenotype

Chromosomal abnormality which involves a reciprocal translocation between the long arms of chromosomes 9 and 22, is associated with chronic myelogenous leukemia

Philadelphia chromosome

Other Hereditary Genes

Other genes that have been found to be associated with hereditary susceptibility to breast cancer: •TP53, PTEN, and STK11. Mismatch repair genes that have been found to be associated with increased risk of ovarian cancer: •MLH1, MSH2, MSH6, and PMS2

CF: Pancreatic Involvement - Endocrine Pancreas (1%)

Pancreatic fibrosis also leads to decreased insulin secretion & number of islet cells •In addition, peripheral insulin resistance has been observed in some pts This leads to Cystic Fibrosis-Related Diabetes Mellitus

Classification of Variants Identified on Gene Sequencing

Pathogenic: strong evidence that the variant is disease causing Likely Pathogenic: moderate to strong evidence that the variant is disease causing Uncertain Significance: insufficient or contradictory evidence regarding disease association Likely Benign: moderate to strong evidence that the variant is not associated with disease Benign: strong evidence that the variant is not associated with disease

What represents the familial relationships among biological relatives that is used to determine the mode of inheritance for phenotypic traits or diseases? **

Pedigree Analysis All affected & unaffected individuals in the family are recorded in a flow diagram (pedigree) using standard symbols •Females: Circles •Males: Squares •Mating: Horizontal line •Consanguinity: Mating between relatives - Double horizontal line •Shading: Phenotype of interest •Patterns •Penetrance

Probability of developing disease in a carrier of a deleterious mutation (usually defined in terms of a given age) **

Penetrance in general individuals with a rare genetic mutation have a higher penetrance, individuals with a common genetic mutation have a lower penetrance Relative risk of developing a major disorder is calculated by the comparison of the incidence of the condition associated by the specific gene mutation among carriers of that mutation in relationship to incidence of noncarriers of the mutation Risk of cancer in individuals with BRCA1 or BRCA2 mutation may be modified by a second gene or by an environmental factor Estimates of penetrance by age 70 yrs: BRCA1 •55-65% for breast CA •39% for ovarian CA BRCA2 •45%-47% for breast CA •11-17% for ovarian CA

Defined as the percentage of individuals who demonstrate the phenotype of a disorder?

Penetrance*** Complete penetrance occurs in diseases where the individual's phenotype reflects the genotype of the disorder. Incomplete penetrance or reduced penetrance occurs when an individual does not exhibit the trait by carries the allele. Incomplete or reduced penetrance occurs in the Emery-Dreifuss MD.

Genetics of CML

Philadelphia chromosome: reciprocal translocation between long arms of chromosomes 9 and 22 - Translocation from chromosome 9 contains proto-oncogenic protein ABL - The resulting gene fusion (BCR/ABL) produces a novel protein that possesses unregulated tyrosine kinase activity → unlimited cell growth and division - Somatic mutations are not inherited - 90-95% of pts with CML have Philadelphia chromosome Pts without Philadelphia chromosome have variant or cryptic translocations that encode for BCR/ABL Philadelphia chromosome is not inherited; people aren't born with it. You can think of control elements like light switches. Let's say you have a light in your hallway that you want to be on all the time. To do this, you get a light switch that is always in the on position. Now what if you accidentally wired your house so that the hallway light switch controlled your bedroom's light? You'd end up with the light always on in your bedroom and very little sleep! This is kind of like what is happening with the Philadelphia chromosome. In this case, 2 genes end up getting stuck together to make a Frankenstein sort of protein. The 2 genes are called Bcr and Abl. This new Bcr-Abl protein can still carry out the job that the normal Abl protein did before it became the "Frankenstein" Bcr-Abl. However, the real problem is that the chromosome's wiring is now all messed up. In our hallway and bedroom light example, Bcr is the light bulb in the hall and Abl is the light bulb in the bedroom. The Abl gene usually has an on/off switch like the bedroom light and the Bcr gene is always on. When Abl was attached to Bcr, it was now put under control of Bcr's control element. The chromosome is rewired so that Abl is always on. And this is much worse than a light that is always on in the bedroom! Abl is normally under tight control because its job is to tell a cell when to divide. You definitely don't want it telling a cell to divide when it shouldn't, because that is one way for a cell to turn cancerous. But that is exactly what happens with the Philadelphia chromosome. The Bcr-Abl protein, which can also tell a cell when to divide, is now always on. So the blood cells divide when they shouldn't. They start making way too many copies of themselves and you end up with CML.

Surveillance guidelines for CF includes?

Population screening

3 stages of Embryotic Development

Pre-embryonic (from fertilization to implantation) Embryonic (implantation through gestational week 8) Fetal (week 8 through birth)

Prior to Genetic Testing for Breast CA

Pre-test counseling is recommended before genetic testing, including: -pedigree evaluation -risk assessment models -discussion of issues for patients such as financial considerations and genetic discrimination Many primary care practitioners might utilize computerized risk prediction model, such as BRCAPRO, to identify appropriate candidates for genetic testing

Additional Standard Pedigree Symbols: Pregnancies/Surrogates

Pregnancies are represented by a diamond with a "P" in the symbol. If the sex is known, write it below the symbol. This symbol is placed directly below the individual carrying the pregnancy. Individuals participating in assisted reproductive technologies (such as sperm or egg donors) are represented in the pedigree with a "D" in their symbol. In this case, the donor provided an egg and is a surrogate or "gestational carrier."

Additional Standard Pedigree Symbols: Pregnancies that end in spontaneous abortion (or miscarriage)

Pregnancies that end in spontaneous abortion (or miscarriage) are represented as a small triangle with their own individual line. This symbol is filled in if evaluation of the fetus is performed and a specific cause (a genetic condition, for example) of the miscarriage is identified. Elected terminations are represented with the same small triangle with a line through the symbol. Again, the symbol is colored in if the fetus is known to be affected by a specific condition. Pregnancies are represented by a diamond with a "P" in the symbol. If the sex is known, write it below the symbol. Note the gestational age if known.

Collection example: Pregnancies added to pedigree

Pregnancy histories may be added to a pedigree. This helps identify individuals with multiple miscarriages or pregnancy losses, histories of infertility, or those who have not chosen to have children for personal reasons

Techniques in which placental or fetal cells are obtained for genetic testing **

Prenatal Diagnostic Testing Unlike prenatal screening, false positive or false negative results do not occur There are risks of adverse outcomes, associated with these techinques 2 common prenatal diagnostic tests: - Chorionic villus samples (CVS) - Amniocentesis Chorionic Villus Sampling (CVS) •Cells from placenta are removed for genetic testing •These cells sometimes don't match fetus: Confined Placental Mosaicism, need to confirm this Amniocentesis: Amniocytes removed transabdominally

In addition to prenatal screening what else can you have?

Prenatal diagnostic testing

Example Indications for DNA Analysis

Presymptomatic detection of Huntington's disease or adult polycystic kidney disease Screening for cystic fibrosis & thalassemias Screening for X-linked conditions such a Duchenne muscular dystrophy & hemophilia A & B Screening for familial polyposis coli

Genetics of Huntington's Disease

Primarily affects Caucasians of NW European descent HD gene on chromosome 4 codes for Huntingtin protein Only human disorder of complete dominance: Heterozygotes and homozygotes affected the same Most cases inherited, but can be due to spontaneous mutation Sex of affected parent plays an important role -Inheritance from father results in disease 3 yrs earlier than inheritance from mother -Juvenile-onset HD almost always inherit gene from father Pic: Pedigree of a human family showing the inheritance of the dominant gene for Huntington's disease. Females and males are represented by circles and squares. Shaded symbols indicate people affected with the disease

Other sickle cell disorders

Sickle cell disease exists in many forms, but HbSS is the MC type, followed by HbSC Non-sickling beta hemoglobin disorders such as thalassemia can interact with sickle cell disease mutation to cause clinically significant disease; these variants of sickle cell disease expression are known as sickle beta-plus thalassemia (HbSbeta+ THAL) & sickle beta-zero

Hx of Genetic Counseling

Profession of Genetic Counseling was born in 1971 w/ the 1st graduating class of master's level genetics counselors from Sarah Lawrence College (in NY) Early genetics "advising," unfortunately, was focused on a eugenics model with the goal of "improving the human race" through forced sterilization of individuals considered "undesirable." It was the advent of amniocentesis for prenatal diagnosis of aneuploidy & newborn screening in the 1960's that created the need for a non-physician clinician to provide information, support, & options for families impacted by genetic conditions The National Society of Genetic Counseling (NSGC) was formed in 1979 In 1994 the American Board of Genetic Counseling (ABGC) took over these activities, & in 2012 the Accreditation Council for Genetic Counseling (ACGC) split off from ABGC as an independent body Now there are over 4,000 board certification genetic counselors in the US & 41 ACGC accredited training programs

Fluorescence In Situ Hybridization (FISH) (testing cells)

Provides information on only 5 chromosomes (13,18, 21, X and Y)

Mortality in CF is generally related to?

Pulmonary failure (ex: pneumonia)

A pedigree illustrating autosomal recessive inheritance

Recessive disorders frequently involve enzymes in metabolic pathways, receptors, or proteins, in signaling cascades Examples of autosomal recessive disorders: Sickle cell anemia Cystic Fibrosis Thalassemia

What provides genetic diagnoses in an increasing number of situations, but are associated with substantial likelihood of uncertain/ambiguous results & incidental findings?

Testing technologies, including microarray, gene panels & whole exome/genome testing

Additional Standard Pedigree Symbols: An affected individual

Represent an affected individual by filling in his/her symbol. If someone is a presymptomatic carrier of a disease-causing mutation (verified by testing), a vertical line is put in his/her symbol. For example, let's say that Huntington disease is inherited through this family. An individual may go forward with genetic testing before the onset of sxs. If testing predicts the later onset of sxs, that person would be represented with symbol for a presymptomatic carrier. Twins come out of the same individual line. To illustrate identical twins (monozygotic), connect the two individual lines with a horizontal line. Fraternal twins (dizygotic) do not have a horizontal line.

The risk that an individual carries an abnormal gene after a negative (normal) screening test result

Residual risk

Hemochormatosis: Hyperpigmentation

Results from a combination of iron deposits in the skin and increased melanin. Hemochromatosis was previously referred to as "bronze diabetes" due to the common occurrence of insulin resistance and darkened skin.

A structural rearrangement involving one or more of the acrocentric chromosomes (13, 14, 15, 21, or 22)

Robertsonian translocation

Testing & Counseling: Hemophilia

Screen all bleeding disorders by PTT, PT, a bleeding time measurement & a platelet count. Order specific coagulation Factor assays based on results from screening.

Expected Serum Iron Values in HHC

Serum Iron----------------Normal to Increased Serum Ferritin-------------Increased TIBC-----------------------Normal to Decreased Serum transferrin saturation--------Increased

Genetic Testing & Counseling for CF

Siblings(additional babies) of an affected proband have •1 in 4 chance of being affected by CF disease •1 in 2 chance of being a carrier of a CF-related mutation-Carriers are generally asymptomatic The American College of Medical Geneticists recommends that carrier screening for CF be offered to all Caucasians of non-Jewish descent & Ashkenazi Jews. •This assessment is accomplished using a panel of 23 different known mutations that occur in high frequencies among the U.S. population.

Mutation in the hemoglobin beta (HBB) gene, leading to a single change in amino acid sequence.

Sickle cell disease

Results from a point mutation in the hemoglobin beta (HBB) gene that causes a single change in the amino acid sequence & results in substitution of valine for glutamine in the Beta subunit of hemoglobin

Sickle cell disease This change confers a new property on hemoglobin, but does not alter how this protein transports oxygen in the blood. Such a change in a gene is known as a novel property - They are anemic not because they are losing blood but because their RBCs don't last the usual 120 days Autosomal recessive Screening of all newborns in the US Sxs begin around 5 months: Fetal hgb replaced by Hgb S •FTT, anemia, splenomegaly, chronic infections •Severe: Vaso-occlusion - Acute chest (MCC of death), CVA, abd pain, priapism Signs •Anemia with target cells (sickling) •Solubility test: Detects HBS (disease or trait) Management •Prevention of crises: Avoid precipitating activities •Dehydration •Physical stress •Infection •Altitude changes •Prolonged exposure to temperature extremes Hydroxyurea •Most commonly prescribed therapy •Improves RBC survival •Lowers WBC: Arrests inflammatory processes •Metabolizes nitric oxide: Vasodilator improves blood flow Allogenic Transplant: The only curative treatment

Who should genetic counseling & testing be offered to in colorectal cancer screening?

individuals with 10-20 or more adenomas identified on colonoscopy in their lifetime and to all first-degree relatives of the index case

Genetics of Sickle Cell Disease

Sickle cell disease is inherited in an autosomal recessive pattern. Because recessive inheritance requires that both alleles be present for disease expression, both defective genes (SS) are needed for sickle cell disease to occur. When offspring inherit one recessive allele (S) and one normal allele (A), they become unaffected carriers (AS). This heterozygous expression of HbS is known as sickle cell trait.

Becker MD

Similar sxs to Duchenne but with a later onset and slower progression. Death usually occurs in the mid-40s. It is most common among males.

Variable Expressivity **

Simply means that the expression of the disease is variable among those who are affected. •Symptoms are variable •Dependent on the percent of normal factor activity

Why is Family Hx apart of diagnostic testing?

Single-gene disorders: Knowledge of family Hx can aid in the dx & tx of rare single-gene disorders such as cystic fibrosis, fragile X syndrome, Huntington disease, or familial hypercholesterolemia. Common, complex diseases: Family Hx has been shown to be a major risk factor for many chronic diseases such as CV disease, DM cancer, osteoporosis, mental illness, & asthma. Family Hx may be the primary risk factor!

What should all couples be asked?

Some basic family hx questions to determine if a referral to a genetic counselor is needed

Pedigree illustrating autosomal dominant inheritance

Square symbols indicate males and circles indicate females; open symbols indicate that the person is phenotypically unaffected, and filled symbols indicate that the phenotype is present to some extent.

Tx of CML: Chemotherapeutic agents (Hydroxyurea)

Supportive option while waiting for definitive diagnosis of CML or pt w/ systemic sxs (concerned of extremely high WBC count causing stroke, death from leukostasis)

Diagnostic Clues to Huntington's Disease

Sxs usually begin around age 30-50 Early sxs-mostly behavioral -Irritability -Moodiness -Antisocial behavior -Psychiatric disturbance -Clumsiness & involuntary facial movements Late sxs -Choreiform movements -Dystonic posturing -Rigidity & akinesia with dementia

Management Options: Chemoprevention if pt chooses to not have prophylactic mastectomies

Tamoxifen- Especially for BRCA2 gene mutation Not as effective as prophylactic mastectomies Not recommended in men

Study of abnormal development **

Teratology Teratogens include anything capable of disrupting embryonic or fetal development & producing malformations The critical period for teratogenic effects is between 3 and 16 weeks of gestation

What is teratology? Teratogens?

Teratology: study of abnormal development Teratogens: include anything capable of disrupting embryonic or fetal development & producing malformations.

Consanguinity: Relationships in pedigree

Terms describing kinship are often confusing. These 3 pedigrees illustrate the relationship of first cousins, first cousins once removed, and second cousins— relationships that are commonly seen in consanguineous matings

Key Diagnostic Elements: Hemophilia

Textbook presentation: A 5-day-old male newborn presents with prolonged bleeding after circumcision. The frequencies of various bleeding sites in hemophilia pts are hemarthrosis in 70%-80% of pts; muscle, 10%-20%; CNS, <5% Frequently encountered examples of moderate hemophilia include muscle hematomas without resultant neurologic compromise and joint bleeding from peripheral sites including the knee, elbow, or ankle

What is a type of teratogen used today to tx MM, erythema nodosum, leprosum, HIV wasting, & apthous uclers?

Thalidomide Originally used as tx for pregnancy-associated morning sickness in the 1950s Removed from market due to teratogenicity, including stunted limb growth in fetus - MC resembling flippers of a seal aka phocomelia Pic:Baby with malformed limbs due to in utero thalidomide exposure

what occurs during the embryonic stage (implantation through gestational week 8) ?

The Blastocyst attaches to the uterine wall 6 or 7 days after fertilization Implantation of the blastocyst may not implant due to: - Endometrial infection - Intrauterine device (IUD) - Morning after pill - Certain genetic mutations Unimplanted blastocysts are absorbed by the endometrium or expelled during menstruation If implantation does occur, by day 14 the uterine endometrium grows over the blastocyst, enclosing it & walling it off from the rest of the uterine cavity - Endometrial cells respond to the attached blastocyst by producing paracrines, such as prostaglandins, that promote local changes in the endometrial tissue Early in the development of the placenta, a layer of cells separates from the ICM (inner cell mass) to form the amnion & a small cavity forms between the ICM & amnion After the amnion is formed, the cells of the ICM differentiate to create 3 distinct germ layers: the ectoderm, the mesoderm, and the endoderm - Their formation marks the beginning of embryonic development & will give risk to the organs by a process called organogenesis

What gene is the only known gene associated with CF?

The CFTR gene Normally, this gene carries instructions for an integral membrane protein that regulates chloride channels in epithelial cells. •Under normal physiological conditions, chloride is excreted & excess sodium uptake is inhibited. •This process maintains the appropriate water balance in secretions. In CFTR mutations, however, this process is disrupted. •In the lungs, this leads to defective chloride transport across the membrane & enhanced sodium absorption. •Results in a net increase in water absorption, thinning of the airway surface liquid, & decreased ciliary clearance. •Bacteria are able to adhere to airway surfaces, proliferate, and resist phagocytosis. Net loss of water that causes these problems of thickened secretions, via lungs, pancreas, bilary tract, etc.

Phenotypic features of Sickle Cell Disease

The abnormal hemoglobin of sickle cell disease (SS) is detectable at birth. Consequently, all states in the United States now require newborn screening for HbS. Affected individuals who test negative on newborn screening or who bypass screening usually present with the disease within the first 2 years of life. Commonly, presenting sxs in babies usually start around 5 months of age as fetal hemoglobin levels drop and are replaced by rising levels of hemoglobin S. Sxs include failure to thrive, pain, anemia, splenomegaly, multiple chronic infections, and swelling of the extremities resulting from vaso-occlusion. Pts who present much more acutely—that is, "in crisis"—may have severe abdominal pain, stroke, acute chest syndrome, renal necrosis, leg ulcers, priapism, or loss of vision due to a massive vaso-occlusive infarction. Multiple studies have shown that vital signs, lab tests and imaging studies are NOT reliable for assessing pain severity or confirming the diagnosis.

What have advantages in genetic & genomic technology led to?

The availability of genetic testing for several thousand conditions, both rare & common

Clinical features of of Osteogenesis Imperfecta

The clinical features are known to range widely with some individuals being asymptomatic simply with a predisposition for fxs (type I disease) to other individuals with sxs such as: -Fxs of no evident cause (even at birth)- Women are at markedly high risk as they are also more prone to developing fxs during pregnancy and post-menopause. -Blue sclera -Progressive hearing loss of adulthood -Short stature- especially in people with Type II -Dentinogenesis Imperfecta (DI)- discoloration of one's teeth, usually a grey or brown color, which easily degrade, break or wear down -Kyphoscoliosis -Respiratory difficulties- due to their small, fragile rib cage and underdeveloped lungs -Mobility impairment -Ligament laxity -Perinatal death in severe cases

Microarray (testing cells)

Uses comparative genomic hybridization to report on gains or losses throughout the genome. It can detect smaller gains or losses than can be found with chromosome analysis. Risks of not being able to detect triploidy and a changes that a variant of uncertain significance will be found.

Clinical diagnosis and testing of Sickle Cell Disease

The complete blood count (CBC) typically demonstrates a normocytic anemia with target cells. When hypoxemia is present, sickled cells are also reported. This finding should prompt the clinician to screen for HbS by using a solubility test. This test causes any HbS that is present to precipitate, but it does not differentiate between sickle cell disease and sickle cell trait because HbS is present in both states. Pic: Peripheral Blood smear

Genetic Testing & Counseling of Muscular dystrophies

The defects in the genetic code for dystrophin, a 427-kd skeletal muscle protein (Dp427), result in the various manifestations commonly associated with MD. Molecular genetic testing is indicated for an individual who has markedly elevated CK levels in addition to dystrophinopathy. Prenatal counseling for pts who are carriers or diagnosed with DMD is recommended. It is recommended that female carriers with a known DNA deletion, duplication, or sequence variant be counseled about the disease

Classifications of Osteogenesis Imperfecta

The disease is classified based on severity, with eight current forms categorized as Osteogenesis Imperfecta I - VIII. -Type 1 is the most mild, and MC, form -Type II is the most severe form -Type III- VIII are varying combinations of type I and II

Segregation of genotypes in the offspring of parents with one dominant (A) and one recessive (a) allele

The distribution of the parental alleles to their offspring depends on the combination present in the parents. Filled symbols: affected individuals

Dx of CF

The dx of CF may be established in individuals with at least 1 phenotypic feature and a mutation in CFTR as evidenced by one of the following: 1) Presence of 2 mutations in the CFTR gene 2) 2 abnormal quantitative sweat chloride tests •Quantitative pilocarpine iontophoresis method 3) 2 transepithelial nasal potential difference measurements. Quantitative Pilocarpine Iontophoresis for Sweat Chloride •Also known as the "sweat chloride test" •Considered the primary test for the dx of CF •90% accuracy Molecular genetic testing is indicated for the following: •Confirming a positive sweat chloride test •Sweat chloride testing is inconclusive or unavailable •Prenatal testing in a high-risk pregnancy •Dx in fetuses demonstrating echogenic bowel on U/S •Assessment of symptomatic newborns not producing adequate volumes of sweat In the rare instance that both sweat chloride testing & mutation testing are either not available or inconclusive: •Transepithelial nasal potential difference measurements may be used to diagnose CF In many cases, newborn screening is performed using the immunoreactive trypsinogen assay •Part of a screening panel routinely applied to blood specimens shortly after birth

Collection example: Ancestries added to pedigree

The incidence of some disorders varies depending on the ancestry of the family. For example, sickle cell disease is MC in African Americans, while cystic fibrosis is MC in Caucasians of Northern European descent. Knowledge of a pt's ancestry should not be the only information used in making a dx, but it should be included in a comprehensive eval of family history. Knowledge of the ancestral background or geographic location of origin is more helpful than ethnicity because it is less subjective. Asking the question, "Do you know where your ancestors came from?" is one way to ask for this info. Consanguinity refers to a couple that is biologically related and has a child (or children) together. Marriage between cousins is a common practice in many parts of the world, although this practice is uncommon in the US. In some cultures, an uncle-niece relationship is a preferred relationship. Children of consanguineous unions are at increased risk for autosomal recessive disorders or birth defects, because close relatives are more likely to share the same gene changes or mutations through a common ancestor than are unrelated individuals. Incest is a term that is usually reserved for the relationship between first-degree relatives, such as a parent and child, or two siblings.

Pseudohypertrophy

The individual's ability to jump & walk are diminished while his or her calf muscles(gastrocnemius) become abnormally enlarged. The physical change is known as pseudohypertrophy. The replacement of muscle tissue with fat & fibrous tissue makes the gastrocnemius-soleus complex appear larger than normal.

Mortality in sickle cell disease is related to?

The number and severity of crises; crises may lead to stroke, acute chest syndrome, complications of anemia, and infections.

Prevalence of Sickle Cell Disease

The overall prevalence of sickle cell disease in the US is approximately 1 in 100,000 and varies by ethnic origin. Among African Americans, the incidence is about 1 in 365, whereas in Hispanic Americans the incidence is 1 in 16,300. The sickle cell mutation is also MC among persons whose ancestry is geographically connected to sub-Saharan Africa, Cuba, South America, Central America, Saudi Arabia, India. and the Mediterranean regions—a phenomenon known as ethnic variation of allelic frequency. An estimated 2 million Americans carry the sickle cell trait.

Genetic Counseling practice areas

The technological advances in genetic & genomic testing have led to involvement of genetic counselors in multiple areas of clinical practice. Genetic counselors are being increasingly viewed as essential members of the health care team in the tx & management pts in many subspecility clinics such as oncology, neurology, cardiovascular, and ophthalmology clinics, in addition to the more traditional pediatric genetic & maternal-fetal medicine settings. In addition to clinical practice, the skills of genetic counselors are being used in non-clinical settings Genetic counselors have become an integral part of the majority of genetic testing laboratories Laboratory counselors act as the liaison between the lab & the ordering provider

Impact of advances in genetics/genomics on genetic counseling

The technological advances over the last 2 decades have dramatically altered the content of these sessions & options available to the pts & families. The 3-billion-dollar Human Genome Project (HGP) - started in 1995, was undoubtedly the spark that launched the genomic revolution. The ahead-of-schedule completion of the HGP led us to understand that rather than the estimated number of 100,000 human genes believed to exist as late as 1988, humans have only ~20,000 genes. -The function of ~8,000 of these genes is known to date The number of genes for which clinical testing is available has risen from 100 in 1993 to close to 6,000 in 2017. Karyotype analysis has been replaced by microarray in the pediatric setting, a technique which uses comparative genomic hybridization to pinpoint sub-microscopic deletions and duplications of the chromosomes which are termed "copy number variants" or CNVs -Microarray has led to a substantial improvement in our ability to provide a diagnosis for individuals with a variety of health, developmental and cognitive challenges In the last 5 yrs, sequencing of the entire exome (regions of the genome that code for specific proteins) & whole genome sequencing (WGS) have greatly influenced the ability to find a genetic dx in individuals for whom standard genetic testing failed for yrs to find an answer. -Between 25-35% of children with a combination of birth defects, developmental delay & dysmorphic features receive a dx through this technology. One of the most significant challenges associated with these advances in genomic & genetic technology is the significant frequency with which genetic findings of uncertain significance are encountered. When we sequence the DNA, there is always the possibility of finding what is known as a "variant of uncertain significance" or VOUS. - When testing for BRCA1/2 first became available, the rate of finding a VOUS was as high as 20%. - 20 years later, this rate is closer to 5% as our understanding and classification of variation in DNA sequence of the gene has improved.

Hemochromatosis: Testing

The wide availability of HFE gene testing has largely eliminated the need for liver biopsy. Testing is performed using polymerase chain reaction (PCR) using a whole blood sample. While most individuals are heterozygous for the HFE mutation and do not develop the disease, they may have abnormal test results. Because sxs of hemochromatosis do not develop until later in life, it is important to identify those at risk for iron over-load. It is reasonable to screen all adult pts with any family history of iron overload or S&S of hemochromatosis. Pediatric screening is not recommended.

Tx of choice for Hemochromatosis

Therapeutic phlebotomy

Hemochromatosis: Tx

Therapeutic phlebotomy, which involves the removal of a portion of the affected individual's blood, is the tx of choice for iron overload in symptomatic pts, as well as asymptomatic pts with a serum ferritin > 1000 micrograms/L or an elevated fasting transferrin saturation Weekly phlebotomy is recommended until serum ferritin reaches approx. 50 micrograms/L & the transferrin saturation is < 50% Chelating agents that bind to iron & prevent its use or deposition in the body are rarely used due to the efficacy of phlebotomy Dietary management should include avoidance of iron containing supplements, limited foods high in iron, and avoidance of excessive amounts of vitamin C which increases absorption of dietary iron Liver transplant is the only tx for pts with end-stage liver disease

Is there currently a specific tx for pts with OI?

There is currently no specific tx for pts with OI, rather management of the associated sxs & regular health screenings in anticipation of future probs

A pedigree illustrating X-linked inheritance

There is no male-to-male transmission Unaffected males do not transmit the phenotype All daughters of affected males are heterozyous carriers

Characteristics of X-Linked Inheritance **

There is no male-to-male transmission of phenotype. Unaffected males do not transmit the phenotype. All daughters of an affected male are heterozygous carriers. Males are usually more severely affected than females. Whether a heterozygous female is counted as affected - & whether the phenotype is called "recessive" or "dominant" - often depends on the sensitivity of the assay or exam. Some mothers of affected males will not themselves be heterozygotes (ex: they will be homozygous normal) but will have a germinal mutation. The proportion of heterozygous (carrier) mothers is negatively associated with the severity of the condition. Heterozygous women transmit the mutant gene to 50% of their sons, who are affected, & to 50% of their daughters, who are heterozygotes. If an affected male mates with a heterozygous female, 50% of the male offspring will be affected, giving false impression of male-to-male transmission. Among the female offspring of such matings, 50% will be affected as severely as the avg hemizygous male; in small pedigrees, this pattern my simulate autosomal dominant inheritance.

Summary of the Detection Rates & False Positives Rates for the Maternal Serum Screens

These are considered screens because none of these are 100%

CF: Pancreatic Involvement - Exocrine Pancreas (99%)

Thickened secretions obstruct the pancreatic ducts, leading to inflammation & pancreatitis Chronic obstruction may lead to fibrosis of pancreatic tissue resulting in pancreatic insufficiency (not enough enzymes) •Decreased digestive enzyme (amylase, lipase) production & inability to digest & absorb nutrients (esp. fats) •Manifests as steatorrhea (dietary fats being excreted in the stool), decline in growth rate, disorders of blood coagulation, skin rashes, & anemia

Describe Risk assessment: Component of clinical genetic counseling sessions

This assessment assists the counselor in determining if genetic testing is appropriate & which genetic tests should be considered Determined based on pedigree (different patterns)

How are genes transmitted from generation to generation?

Through chromosomes

An example of Consanguinity pedigree

To illustrate a consanguineous relationship, use a double line between the two individuals. If known, note the degree of relation above the double lines.

Prognosis of CML

Using tyrosine kinase inhibitors & other molecular target agents: - >90% of pts remain alive w/o disease progression at 6 yrs - disease can be controlled long-term by oral agents Factors affecting prognosis: - Age - Phase of CML - Cytogenetics - Comorbid diseases

Collection example: identifying pt, their 1st, 2nd, & 3rd degree relatives, and info on maternal & paternal relatives with added info

To the basic "skeleton" of the pedigree, we have added info about current ages of those who are still living, ages at death & causes of death for those who are deceased, & some basic relevant health info. Relevant info may change for each pt. As another slide will address, the information collected can be comprehensive (including general diagnoses or health status) or targeted for specific health conditions, such as cancer.

Overview of Muscular Dystrophies

Together DMD & BMD affect 1 in 3,500 to 5,000 newborn males worldwide. In the US between 400-600 boys are born with these conditions each year. DMD is inherited in an X-Linked Recessive pattern - Each son born to a mother who is a carrier of the defective gene has a 50% chance of acquiring DMD. - Each daughter born to a mother who carries the defective gene has a 50% chance of becoming a carrier. Men with DMD cannot give the defective gene to their sons because they donate the Y chromosome that does not carry the gene.

Pathogenesis of Hereditary Breast & Ovarian CA

Tumor suppressor genes •Function is to suppress cellular proliferation •This function can be lost through chromosomal aberration leads to susceptibility to neoplasia. Germline mutation •A change in a gene in the body's reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. •Appearance of CA depends on where 2nd mutation occurs •CA can seem to "skip" a generation within a family •When germline mutation occurs, there's a 50:50 chance of passing the mutation on to the next generation Tumorigenesis •Loss of both copies of tumor suppressor genes is permitted to cause neoplasm •Tumor development requires mutations in multiple growth control genes to manifest •Chemical, physical, biological environmental exposures or chance errors can cause cell replication

Associated Syndromes of Hemochromatosis

Type 2 HH Type 3 HH Type 4 HH African (Bantu) iron overload Neonatal Hemochromatosis Secondary Iron overload syndromes

Clinical features of Osteogenesis Imperfecta based on Types

Type I- often shown to have a distinct mottling pattern on skull radiographs due to the small islands of irregular ossification, where as type II is so severe, in utero or immediately post-partum complications or are commonly seen. -The immense fragility of the connective tissue frequently leads to incomplete bone formation, or ossification, multiple stages of rib fracturing or beading, and crumpled long bones (known as acoordina femora). - he said won't be on test.... Types III and IV- the slightest physical trauma can create severe consequences such as deformity. These types also have the appearance of popcorn deposits on the ends of long bones. It develops from the over abundance of mineral deposition at these sites and can lead to further complications. Type V- recognized by the presence of dislocated radial heads and hyperplastic callus formation. Type VII- Rhizomelia (disproportion in length of proximal limb, shorter than normal men) & coxa vara (deformed hip joint, where neck of femur is bent downward and acute angle of femoral head is < 120 degrees & affects hip socket) are observed.

What are the 3 major categories of Prenatal Genetic Screening? **

Ultrasound Maternal serum screening Noninvasive prenatal screening (NIPS) Also includes: First Trimester Screen Quad Screen Sequential/Integrated Testing Twins and Prenatal Screening Ultrasound: •Presence of absence of birth defects •Soft markers: Subtle changes that alter risk for specific aneuploidy Maternal serum screening: hCG, AFP First Trimester Screen: PAPP-A, hCG, AFP Combined First Trimester Screen with Ultrasound Quad Screen: hCG, estriol, inhibin, AFP Sequential/Integrated Screening: Combines 1st and 2nd trimester screens Noninvasive Prenatal Screening: cell-free DNA (cfDNA)

Sickle Cell Manifestations

Vaso-occlusinve Crisis (VOC) Acute Chest Syndrome (AChS) Acute Anemia Infarction and Embolic complications Infection/Sepsis Priapism

What is found in fruits & veggies, as well as animal liver (highest amounts), that has been shown to cause birth defects?

Vitamin A/Retinoic Acid Isotretinoin (Accutane), a vitamin A isomer, used as tx for cystic acne is considered to be one of the most potent teratogens in widespread use - Malformations typically involve the cranium & face, heart, CNS, & thymus Women are advised to use 2 forms of birth control while on these types of meds and be apart of a database such as iPledge

Genetic counseling: Sickle Cell Disease

When counseling high-risk individuals, it is important to consider other beta-chain disorders that may contribute to sickle cell disease. (ex: thalassemia) The carrier states for hemoglobinopathies other than HbS may be unknown in those persons who have never been screened for these abnormalities. The optimal time for counseling is during preconception family planning. When pts present after conception, early testing is important. Prenatal diagnosis for those at increased risk is possible through amniocentesis. However, because there is wide variation in clinical presentations among affected individuals, it is impossible to predict the extent or outcome of sickle cell disease.

Sxs of Sickle Cell Disease

When red cells deoxygenate, the HbS chains are transformed into rigid polymers, which results in rigid, crescent-shaped red blood cells. These "sickled" cells are unable to flow freely through small vessels, which results in pain and ultimately vaso-occlusive infarctions in multiple organ systems. Pain, infections, and bone infarctions are hallmark clinical presentations of sickle cell disease, along with varying degrees of anemia.

Additional Standard Pedigree Symbols

When representing multiple females or males, simply write the # of individuals within the sex symbol (such as with the "2 males" and "4 females"). If sex is unknown or a combo of males & females, use a diamond. Represent an unknown # of individuals or multiple individuals of both sexes with an "N" in a diamond. Two lines at the bottom of the line of descent is used when an individual has no children because of infertility. If known, note the cause of infertility at the bottom of the lines.

With Lynch syndrome or suspected attenuated familial adenomatous polyposis, screening should be done with? Why?

With colonoscopy rather than flexible sigmoidoscopy because polyps are not evenly distributed throughout the colon.

Can disease or conditions that result from the action of alleles at one gene (monogenic) still be influenced by other loci in a person's genome?

Yes!

Arthropod-borne flavivirus that is transmitted by mosquitoes & sexual intercourse?

Zika Virus Zika Causes: miscarriage, microcephaly, developmental delays, myelitis, memingoencephalitis & Guillain-Barre syndrome

F8 and F9 gene mutations

are inherited in an X-linked recessive pattern, with only males affected by the resulting hemophilia; females are carriers of the mutations but rarely develop the disease itself.

What happens during the pre-embryonic stage (from fertilization to implantation)?

Zygote undergoes rapid cellular division & is converted into a solid ball of cells: Morula - Repeated cell cleavage 3-4 days after fertilization that yields a total of 16-32 cells Fluid accumulates in morula creating a hollow sphere: Blastocyst - Consists of a clump of cells, the inner cell mass, which eventually becomes the embryo, & a ring of flattened cells, the trophoblast - The trophoblast further develops into the embryonic portion of the placenta that supplies nutrients to & removes wastes from the embryo

Main cause of Muscular dystrophy?

a defective gene located on the X chromosome that is responsible for the lack or absence of a protein called dystrophin.

Associated Syndromes of Hemophilia: Hemophilia B Leyden

a rare variant of hemophilia B inherited in an X-linked pattern

Common sxs of Hemochromatosis

abdominal pain, fatigue and arthralgias.

Of the women with breast CA what percentage have 1 or more first-degree relatives who have been affected by breast cancer?

about 10-20%

Homologous copies of a gene are termed? **

alleles (homozygous or heterozygous)

What does prenatal genetic screening refer to? **

any "test" that is not diagnostic

What is the critical period for teratogenic effects?

between 3 and 16 weeks of gestation

Homozygous translocation

both pairs interchanged

Associated Syndromes of Hemophilia: Hemophilia C

deficiency of Factor XI (rare) 2nd only to von Willebrand's disease among bleeding disorders affecting females. Also known as Plasma Thromboplastin Antecedent (PTA) deficiency

What does Biochemical analysis do? **

determines if certain proteins are present or absent looks for enzymatic defects "Inborn errors of metabolism" - produce a metabolic block: - Phenylketouria (PKU) - Cystic Fibrosis Biochemical Analysis •Determines if certain proteins are present or absent •Used to identify enzymatic defects

What are 3 factors known to affect the likelihood & extent of teratogenesis?

dosage time of exposure genotype of the embryo

When doese Sickle cell disease typically present?

early childhood in the US, identified through required newborn screening

Majority of providers are able to dx based on a few clinical features such as?

fragile bones or multiple fxs- usually without cause or unsubstantial force, blue sclera, vary stature size, progressive hearing loss & possibly dentition problems.

Persons with cirrhosis have an increased risk of?

hepatocellular carcinoma

Evaluation of a person with newly diagnosed hemophilia A or B should include?

identification of the specific mutation, a personal hx of bleeding, family history of bleeding, a thorough musculoskeletal evaluation, associated disease screenings, and baseline laboratory tests.

Blood Stem cell diagram

in CML excess # of granulocytes that are uncontrolled

Tx of CML: Allogenic hematopoietic stem cell transplantation

is the only curative therapy Best results (50-85% remission): - Pts < 50 yrs - Transplanted in chronic phase within 1 year of dx - Human leukocyte antigen (HLA) matched sibling donor Risk: graft-versus-host disease, graft rejection

Majority of Alzheimer's disease cases are?

late onset or sporadic, usually developing after age 65

Exact location of a gene on a chromosome is known as its? **

locus

What does nondisjunction result in?

loss or gain of a chromosome

What is transported from the nucleus to the cytoplasm, where its genetic info is used to manufacture proteins (translation)?

mRNA

Dx of Osteogenesis Imperfecta

mainly clinically based - Practitioners presented with a pt who has multiple features of OI, is generally sufficient to make the dx; this includes but is not limited to the presence of blue sclera, progressive hearing loss, short stature, bone fragility or multiple fractures, dentinogenesis imperfecta, ligamentous laxity or a FHx of the disease. - Radiographic features are major findings present and have a tendency to vary with age and severity of disease. •"Codfish vertebrae"- the consequence of many spinal compression fxs, seen more commonly in adult pts. - **Rule out other more common causes of fractures first, such as nutritional deficiencies, malignancies or even battered child syndrome.** Individuals, regardless of the type of OI - with the exception of type I- with which they have been diagnosed, have a decreased bone mineral density usually with varying degrees of osteopenia. - The specific degree or range of degrees for specific type is difficult to conclude due to the increase in likelihood of limited exercise due to more recurrent fractures in some forms of OI which in turn increases the degree of osteopenia. - While bone density may be detected through the use of dual energy x-ray absorptiometry (DEXA), bone density may appear to be normal due to the fact that the DEXA measures mineral content as opposed to collagen content.

Advanced disease of Hemochromatosis

manifests as hepatomegaly, hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiomyopathy, hypogonadism, arthritis, and hyperpigmented skin

Alzheimer's disease typically presents with early problems in?

memory & visuo-spatial abilities

In addition to these nuclear chromosomes what does each mitochondrion (organelle found in varying #'s in cytoplasm of all cells) contain?

multiple copies of a small chromosome This mitochondrial chromosome encodes a few of the proteins for oxidative metabolism & all of the transfer ribonucleic acids (tRNA) used in translation of proteins w/in this organelle.

What tests involves an invasive procedure & has a risk of miscarriage?

prenatal diagnostic testing

What tests are not diagnostic & have false positives & false negatives?

prenatal screens

Course of Hereditary Hemochromatosis

primarily HFE gene type 1 (C2A2Y)

Screening tests for hemophilia include?

prolonged activated partial thromboplastin time with normal prothrombin time, normal bleeding time, and normal fibrinogen levels.

While the majority of patients whom suffer from OI inherit the disease through an autosomal dominant, some are subjected to?

random gene mutation

What can increase an individual's lifetime risk of colon cancer approximately 2-fold?

risk of colon cancer in a first-degree relative of an affected individual

Dx of CF is made using?

screening methods & specific mutation testing

Associated Syndromes of Hemophilia: Acquired hemophilia

similar to inherited Hemophilia, but due to autoanitbodies and usually first appears in adulthood.

Diagnosis of hemophilia is made by?

specific factor assays

Hemophiliacs frequently present with?

spontaneous bleeding into joints (hemarthroses) and muscles (hematomas), and experience variable degrees of prolonged or abnormal bleeding.

Almost all CF-affected males are infertile due to?

the absence of spermatozoa (azoospermia) •Results from the congenital absence of the vas deferens or other supportive structures. Congenital absence of the vas deferens can occur as the only feature of a CFTR mutation in men w/o pulmonary or gastrointestinal sxs. (typically not dx until later in life due to infertility issues) Females with CF are generally ovulatory, but may experience difficulty becoming pregnant if they have abnormal cervical mucus.

Deletions, nonsense mutations, frameshift mutations, and splice site mutations of the CFTR gene result in?

the complete absence of a functional CFTR •Represents the majority of CF mutations Missense mutations appear to only partially alter the function of CFTR. •Missense mutations often present later in life and may be associated with a milder disease course. It is this variety of mutations in the CFTR gene that is responsible for the variable clinical phenotypes. •The amount of functional CFTR seems to determine the clinical presentation & course of disease. (Table 11-1)

Serum ferritin and transferrin saturation have?

the greatest sensitivity and specificity as biomarkers for Hemochromatosis

What happens in chronic myelogenous leukemia?

too many blood stem cells develop into abnormal granulocytes

When does colorectal cancer occur?

when cells that line the colon or the rectum become dysplastic and undergo uncontrolled proliferation

3rd step of Collection: Elicit the following info for individuals represented in pedigree:

•Age, birth date, or year of birth •Relevant health information •Diagnosis, age at diagnosis •Age at death, or years of birth/death •Cause of death •Ethnic background for each biological grandparent •Infertility, or no children by choice •Consanguinity •Pregnancies •Pregnancy complications (note gestational age): Miscarriages, stillbirths, ectopic pregnancies, pregnancy terminations, preterm birth, preeclampsia, bleeding/clotting complications

Dx- Later S&S of Muscular Dystrophies

•Inability to walk •Shortening of muscles and tendons •Limited movement •Breathing problems •Abnormal curvature of the spine •Cardiac abnormalities •Difficulty swallowing - Can cause aspiration pneumonia

Klinefelter syndrome: XXY **

•Incomplete masculinization •Small genitalia/testes •May be mosaic (less severe) •"pear-shaped mama's boy"

Step 2 of Collection: produce at least a 3-generation pedigree that includes:

•Pt's 1st-, 2nd-, & 3rd-degree relatives •Info on maternal & paternal relatives •Representation of "full" from "half" relationships ex: children with same or different partner •Affected & unaffected relatives Identification of the historian, or person providing the info (may be the pt or someone else, such as a parent) Date of collection (or date of update), & name of collector (or updater) Legend or key, if symbols are used to designate disease

Dx - Initial S&S of Muscular Dystrophies

•Waddling gait (Myopathic Gait) •Pain or stiff muscles •Difficulty with running & jumping •Walking on toes •Difficulty sitting up or standing up •Learning disabilities

Turner syndrome (monosomy)**

•XO •Short stature, normal intellect, infertile