MEDS 245 - Spring 2185

47, XXY and 47, XXX

- 1/1000 births - both do not have distinctive phenotypes - usually physically normal, slightly taller than siblings and may have learning disabilities though IQ is normal

Klinefelter Syndrome

- 1/500 males - may appear normal until puberty - learning disabilities common despite normal IQ - fertility issues - testosterone treatment available

Unbalance Rearrangements: Deletions

- 1/7000 live births - leads to partial monosomy - material lost within the arm of the chromosome Terminal: from the end of the chromosome Interstitial: from the middle portion of the chromosomal arm

Birth Defects

- 1:28 parents receive this news - over 6,000 known birth defects - cause is unknown in 60% of cases

Imprinting

- 60-100 genes demonstrate control of gene expression according to the parent of origin - the imprinted gene is inactivated - disease may occur when the imprinting mechanism does not function properly

Multigenic Effects

- AKA Polygenic - Multiple loci that affect phenotype

Vectors

- DNA molecules into which the gene or other DNA fragment of interest is cloned - capable of replicating in a particular host

FISH

- Fluorescent In-Situ Hybridization - fluorescent dyes are used to visualize chromosomal aberrations

Important terms in Cytogenetics

- Karyotype - Aneuploid vs Euploid - Trisomy vs Monosomy vs Triploidy - Chromosome vs Sex Chromosome Abnormality - Mosaicism

Multifactoral Inheritance: Quantitative

- a measurement - normal range - familial aggregation - heritability

Genetic Counseling: Job

- a medical appointment which deals with the occurrence or recurrence of a genetic disorder in a patient or family - patients can be seen just once or followed over time

Chromosome

- a single, very long strand of DNA, tightly coiled up - 23 pairs - 2 are the sex chromosomes, X and Y - smallest chromosome is 21

Options During Pregnancy: Invasive

- amniocentesis (2nd trimester, >15 weeks) - CVS (first trimester, 10-12 weeks) - cordocentesis

Comparative Genome Hybridization

- another fluorescent imaging technique - used to measure the difference between 2 different DNA samples in copy number of a particular DNA segment

Genetics

- began in the 20th century - a medical specialty whose concepts and approaches are important in the diagnosis and management of disorders

Oogenesis

- begins during prenatal development - several million oocytes at the time of birth - 400 eventually mature and are ovulated

Uniparental Disomy

- both copies of the same chromosome are inherited from the same parent

BRCA1 and BRCA2: Management Guidelines for Women

- breast awareness starting at 18 - clinical breast exam, every 6-12 months starting at 25 - annual breast MRI with contrast 25 - 29 - annual mammogram and breast MRI 30 - 75 - manage on an individual basis 75+ - discuss option of risk-reducing mastectomy (RRM) - recommend risk-reducing salpingo-oophorectomy (RRSO) typically 35 - 40

Indicators of Hereditary Breast and Ovarian Cancer Syndrome (HBOC)

- breast cancer before 45 - premenopausal BC - "triple negative" BC - ovarian cancer - male BC - 2 primary BCs - both breast and ovarian cancer in the same individual - 2 or more BCs in the same family, when one is under the age of 50 - Ashkenazi Jewish Heritage - prostate cancer - melanoma - pancreatic cancer - serous uterine cancer

BRCA1 and BRCA2: Management Guidelines for Men

- breast self-exam training and education beginning at 35 - clinical breast exam, every 12 months beginning at 35 - recommend prostate screening for carriers of either BRCA1 or 2 at 45

1st Trimester Ultrasound

- confirm intrauterine pregnancy - confirm viability - vaginal bleeding - concerns for ectopic pregnancy - estimate gestational age - abnormal serial hCg levels or bloodwork - Nuchal translucency measurement Evaluate: - mean sac diameter - crown-rump length - nuchal translucency - amnion and chorion, specifically as they relate to multiple gestations

Medical Roles

- determine if family/individual has an increased chance for a genetic condition - diagnose a genetic condition - aid in the management of a genetic condition

Medical Genetics

- diagnosis, management, and treatment of human disease that is at least partly hereditary in origin - focuses on the patient within the context of an entire family

Mitosis

- ensures each of two daughter cells receives a complete set of genetic information Prophase Prometaphase Metaphase Anaphase Telophase

Autosomal Dominant Inheritance

- equally affects males and females - dominant = 50% inheritance chance - one copy of mutated gene will result in an affected individual - vertical inheritance pattern (e.g. Huntington's Disease)

Autosomal Recessive Inheritance

- equally affects males and females - recessive = 25% inheritance chance - needs 2 affected genes - horizontal inheritance pattern (e.g. Cystic Fibrosis)

Supportive Roles

- explain scientific information in meaningful and practical terms - provide emotional support - assist the family/individual in consideration of testing options - locate outside resources and aid families in using them

Genomic Imprinting

- expression of disease depends on whether abnormal chromosome was inherited from father/mother - must be reversible - controlled by imprinting center (e.g. PWS, Angelman, BWS)

Non-Penetrance

- failure to manifest despite molecular analysis or family history - may cause the phenotype to skip a generation

Genetic Counseling: Breast Cancer Related

- family/personal history - overview of genetics - testing process and logistics - associated cancer risks - medical management options - implications for family members - impact on insurance

Spermatogenesis

- formation of sperm - takes about 64 days - 200 million per ejaculate - initiated at puberty

X-Linked Inheritance

- gene is on X Chromosome - affects males and females unequally - mother carries affected gene - men will not pass to sons, but will pass to daughters - Diagonal or X inheritance pattern (e.g Fragile X syndrome)

2nd Trimester Ultrasound

- genetic sonography - detailed fetal anatomy scan (19-22 weeks) - bleeding - follow up from amniocentesis, CVS, or blood work - genetic referral - SGA/LGA - maternal high risk - fluid volume - multiple gestation - dating in late prenatal care - cervical concerns

Trisomy 18

- incompatible with long term survival - 1/3000 live births Phenotypes: microcephaly, small face, low set ears, micrognathia, omphalocele, congenital heart disease, club foot, curled in hands

Trisomy 13

- incompatible with long term survival - 1/5000 livebirths Phenotypes: pugilisitc appearance, midline defects including holoprosencephaly, cleft, congenital heart disease, polydactyly

Essential Elements of Screening

- it is NOT diagnostic - should be cost effective and low risk - maximize detection at and minimize screen positive rate - screening identifies a population of patients at higher risk for a disorder

Risk Stratification: Familial Cancer Risk

- likely caused by a combination of genetic and environment factors

Unbalance Rearrangements: Isochromosomes

- missing one arm and the other is duplicated in a mirror image - partial monosomy and partial trisomy

De Novo Mutations

- new mutation - in some cases, there is no family history - each condition must begin somewhere and in someone

Risk Stratification: General Population

- occurs by chance - negative for a known deleterious mutation in the family

Risk Stratification: Hereditary Cancer Risk

- occurs when an altered gene is passed down from parent to child - more likely to have relatives with the same or related types of cancer

Achondroplasia

- one of the most common causes of short stature, average body size with shorter limbs - produce less cartilage = shorter bones - have an altered version of a gene, called FGFR-3 - born to parents of average height, often APA - mutation caused by single letter change in DNA code

Top 3 Autosomal Disorders

- only 3 well defined (non-mosaic) chromosome disorder compatible with postnatal survival Trisomy 21, 18, 13 - all involve growth retardation, mental retardation, and MCA

Turner Syndrome

- panethnic - complete or partial absence of a second X chromosome - not associated with AMA or APA - phenotypes include: cystic hygroma lymphedema broad chest cardiac defect (50%) renal anomalies (60%) hearing deficit short stature (100%) infertility (90%) normal intellect

Variations in Dominant Phenotypes

- penetrance - variable expressivity - De Novo Mutations - Mosaicism - Phenocopy

Common Timeframes for Referral

- prenatal - postnatal - pediatrics - adulthood

Multifactoral Inheritance: Qualitative

- present vs absent - familial aggregation - concordance vs discordance (same vs different phenotype) - relative risk - case control studies

Relative Risk

- prevalence of the disease in the affected person relatives or in the general population - increased by the presence of more than one affected relative, a severe form, or an early onset of the disorder

Amniocentesis

- procedure that inserts a needle into the amniotic sac - removes a sample of fluid - 1/300 risk of complication - >15 weeks - approx. 2 weeks for results

Chorionic Villus Sampling (CVS)

- procedure that inserts a needle into the placenta (chorionic villi) - either transabdominal or transcervical - 1/90 risk of complication - increased chance of Maternal Cell Contamination - 10-12 weeks only - approx. 2 weeks for results

Meiosis

- process by which diploid cells give rise to haploid gametes - cell division is unique germ cells Meiosis 1: reduction divison - chromosome number is reduced by half and recombination occurs Meiosis 2: two daughter cells divide to form four haploid cells

Human Genome

- purines: Adenine and Guanine - pyrimidines: Thymine and Cystosines

Trisomy 21 - Down Syndrome

- single most common genetic cause of MR - 1/700 babies are born with DS with AMA effect - 20-25% of DS conceptuses survive to brith Phenotypes (variable): hypotonia, short stature, flat occiput, short neck with loose skin, flat nasal bridge, low set ears, open mouth with protruding tongue, epicanthal folds, up-slanting palpebral fissures, simian crease, clinodactyly

Options During Pregnancy: Non-Invasive

- ultrasound - maternal serum/screening/triple screening - first trimester screening - isolation of fetal cells from maternal circulation

First Trimester Screening

- ultrasound markers: nuchal translucency - serum markers: hCG or free beta-subunit / PAPP-A (pregnancy associated plasma protein a)

Fertilization

- usually takes place within a day or so of ovulation

Unbalance Rearrangements: Marker/Ring Chromosomes

- very small, unidentified chromosomes - supernumerary chromosomes - extra structurally abnormal chromosomes

Characteristics of Complex Diseases

-genes contribute, but are not single gene disorders, and often demonstrate familial aggregation - relatives of an affected person are more likely to have predisposing alleles - disease more common among the close relatives of the proband/less common among distant relatives (e.g. identical vs. fraternal twins)

Preimplantation Genetic Diagnosis

1. using IVF techniques 2. remove one or two cells for testing 3. test DNA or chromosomes 4. result: genetic disorder excluded = embryo implanted 5. result: genetic disorder detected = embryo discarded

Which Chromosome(s) does BRCA1 and BRCA2 effect?

BRCA1 - 17 BRCA2 - 13

Genes and Chromosomes: Pathway

Cell Nucleus Chromosome DNA Strand Gene Code

Mathematical Equations

Dominant = 1/2 (# of people away) till you reach your generation you are testing for. Recessive = Both parents are carriers - 3 part equation (P)x(M)x(1/4RR) Both Carriers: (1/P)x(1/M)x(1/4) = 25% Relative Risk - Carrier = 1/2 Relative Risk - Affected = 1/4

Gravida and Para

G__P__ __ __ __ G = # of pregnancies P = __ __ __ __ 1. full term 2. pre term 3. abortions 4. live born

Modifier Genes

Genes that affect the occurrence or severity of a Mendelian disorder

Balance Rearrangements: Translocations

Reciprocal: total chromosome number unchanged / common de novo rearrangements that occur randomly throughout the human gene Robertsonian: most common type / fusion of two acrocentric chromosomes near the centromere (45 chromosomes) (e.g. Turner Syndrome)

Empiric Risk

Risk observed in other similar families

Mosaicism: Somatic vs Germline

Somatic: new mutation occurs in the non-gamete forming cells of the body (limited to individual) Germline: new mutation occurs in the cells that ultimately form the gametes (can occur in future generations)

Balance Rearrangements: Insertions

Three breaks; rare

Mosaicism

Variation of genetic composition between some cells / chromosome abnormalities are usualy present in all cells Somatic: variation among the different body cells Germline: variation within the gametes of an individual

Mutation

a change or an alternation in the gene

Libraries

a collection of recombinant clones from a source known to contain the gene

Pedigree

a diagram that shows the occurrence and appearance or phenotypes of a particular gene or organism and its ancestors from one generation to the next

Southern Blotting (DNA)

a filter to which DNA has been transferred to separate DNA molecules by size

Northern Blotting (RNA)

a filter to which RNA has been transferred to separate RNA molecules

Gene

a segment of DNA that codes for a protein, which in turn codes for a trait

Alleles

alternative forms of the gene

Cordocentesis

blood transfusion through the umbilical vein of the placenta

Chromosome Disorders

defect due to an excess or a deficiency of all or part of a chromosome

Variable Expressivity

different features evident in different members of the family (e.g. Neurofibromatosis Type 1)

Restriction Enzymes

enzymes that recognize specific double-stranded DNA sequences and cleave the DNA at or near the recognition site

Heritability

fraction of the total phenotypic variance of a quantitative trait that is caused by genes

Prader-Willi Syndrome

genital hypoplasia neonatal hypotonia feeding difficulty obesity short stature small hands and feet Chromosome 15q11 - q13 - absent paternal allele

Single Gene Defects

individual mutant gene

Obligate Carrier

individual who has a non-penetrant condition who has affected children

Molecular Cloning

isolate a particular gene in large quantities for further study

Unbalance Rearrangements: Duplications

leads to partial trisomy

Penetrance

likelihood that a characteristic manifests itself

Quantitative PCR

measures in real time the increase in the amount of PCR product being made

Angelman Syndrome

mental retardation microcephaly ataxic gait inappropriate laughter seizures Chromosome 15q11 - q13 - absent maternal allele

Multifactorial Inheritance

multiple genes combined with environmental influences

Phenotypes

observed physical characteristics of the gene

Phenocopy

occurrence within a family of a phenotype that is similar to a particular disorder but developed in the absence of an inherited genotype

Familial Clustering

recognizing that family members share a greater proportion of their genetic information and environmental exposures than do individuals chosen at random

Balance Rearrangements: Inversions

single chromosome undergoes two break and segment inverts paracentric = not including centromere pericentric = includes centromere

Founder Populations

small number of people originating a population; one of whom had a mutation

Beckwith-Wiedemann Syndrome

somatic overgrowth LGA infants enlarged organs umbilical hernia predisposition to tumors Chromosome 11p15 - 50% imprinting center defect - 20% uniparental disomy

Genetic Counseling: Definition

the counseling of individuals with established or potential genetic problems, concerned with medical management or potential risks to future offspring

Screening

the identification of those who are sufficiently at risk of a specific disorder to justify a subsequent diagnostic test or procedure, or in certain circumstances, direct preventive action

Frequently Occurring Alleles

the more commonly an allele occurs in a population, the more likely the recessive trait is to appear in multiple generations

Unbalance Rearrangements: Dicentric Chromosomes

two fused chromosome segments fuse end to end