Genetics

Question 1

Autosomal Recesive

Answer 1

Horizontal transmission, males and females equally affected, risk of recurrence in sibling is .25, family history negative

Question 2

Autosomal Dominant

Answer 2

Vertical Transmission, Males and females are equally affeted, risk of recurrence in sibling is .5, could be due to new mutation

Question 3

X-linked recessive

Answer 3

trait is usually expressed only in males, both parents are normal, if mother is carrier, .5 of daugthers will be carriers and .5 of sons will be affected; ex. red-green color blindness, G6PD deficiency

Question 4

X-linked dominant traits

Answer 4

Trait is expressed in males and females, no father to son transmission

Question 5

Haplotype

Answer 5

a unique combination of genetic markers present on a chromosome

Question 6

linkage disequilibrium

Answer 6

2 loci are in linkage disequilibrium when their alleles are not randomly associated

Question 7

Polymorphism

Answer 7

the occurence of 2 or more allelic traits in a population with frequencies of at least 1-2%

Question 8

Multifactorial/Threshold model

Answer 8

Multiple genes and environmental factors contirbute to individual’s liability to the trait

Question 9

Heritability

Answer 9

Fraction of the total phenotype variance that is attributable to genes

Question 10

Mixed model

Answer 10

a major contribution from one gene, polygenic contribution, and environmental component

Question 11

Conditions for Hardy-Weinberg Equilibrium

Answer 11

Infinitely large population
Random Mating
No selective advantage
No mutation, migration or genetic drift

Question 12

Autosomal Recessive Disorder

Answer 12

Tay-Sach’s- macular cherry red spot, hyperacusis, progressive weakness and hypotonia. Loss of hexoaminosidase A (loss of hex A allele), GM2 catabolic deficiency

Mucopolysaccharidosis I- depressed nasal bridge, bulgin forehead, protruding skull, vertebral abnormality, short wider bones in hand. Due to buildup of GAG’s

Other’s- urea cycle deficiency, propionyl CoA carboxylase deficiency, loss of biotin recycling (decrease in holocarboxylases), galactosemia(gal-1-P uridyltransferase), I- cell disease (lose mannose-6-phosphate recognition marker)

Question 13

Allelic/Locus Heterogeneity

Answer 13

Allelic- different alleles at locus that produce different phenotypes (Hurler/Schei)
Locus- mutations at different loci produce identical phenotypes (San fillippos)

Question 14

Prader Willi

Angelman

Answer 14

Genetic cause: Uniparental disomy for maternal chromosome 15 or deletion of paternal chromosome 15
Clinical Manifestation: obesity, hypotonia, small hands and feet, insatiability

Genetic cause: Deletion of Maternal chromosome 15
Postnatal growth deficiency, severe mental retardation, ataxia, seizures

Question 15

Autosomal Dominant Disorders

Answer 15

Familial Hypercholestrolemia (defective receptors example of haploinsufficiency)
Insulin Chicago (dominant negative)
Osteogenesis imperfecta (type one collagen, protein suicide)
Achondroplasia (gain of function of FGF receptor which inhibits chondrocyte proliferation)
Wolf-Hirschhorn Syndrome (haploinsufficiency of FGFR3 gene)
Familial Male Precocious Puberty (gain of function of LH receptor pathway)

Question 16

Trinucleotide repeat diseases

Answer 16

Friedreichh’s Ataxia- loss of function, autosomal recessive, chromosome 9, associated with GAA repeat in 1st intron, onset typically before 20 years

Myotonic Dystrophy- autosomal dominant, CTG repeat of chromosme 19, progressive weakness andmyotonia

SBMA- CAG repeat in first exon of X chromosome,
toxic to spinal cord and bulbar motor neurons, also leads to partial androgen sensitivity

Huntington’s Disease- autosomal dominant disorder, CAG repeat, dementia, gain of function

Question 17

Target organs for Mitochondrial disorders

Answer 17

Nervous system, skeletal muscle, cardiac muscle

Question 18

MELAS

MERRF

NARP

Answer 18

point mutation, childhood onset, seizures, myopathy, recurrent headaches
Myoclonic Epilpsy with Ragged Red Fibers

Neuropathy, Ataxia, Retinitis Pigmentosa

Question 19

Heteroplasmy

Threshold Effect

Answer 19

mosaicism with a single cell of mtDNA, genetic drift on a cellular level
Dependence on aerobic metabolism is correlated with sensitivity to mtDNA mutation

Question 20

In vivo

Ex vivo

Answer 20

Direct Delivery, Delivery into differentiated nondividing cells as well as dividing cells, episomal, unstable, treatment may need to be repeated (CFTR)

Genes introduced into patient’s cells in vitro and returned, gene transfer requires cell division, integrates into host genome, stable, gene persists for life (SCID)

Question 21

Chromosome Abnormalities

Answer 21

Trisomy 21- nondisjunction, mosaicism, or translocation, 1:600, hypotonia, CNS deficit, congential heart disease, duodenal atresia

Trisomy 18- 1:3000, early mortality, severe mental retardation, migrognathia, clenched fist/hand, poor hip abuction

Trisomy 13- 1:5000, early mortality, incomplete forebrain development, retinal dysplasia, severe mental deficiency, cleft lip/palate

Turner’s Syndrome- mosaicism, 1 gamete (X) and 1 gamete (O), 1:2500, short stature, poor social cognition, ovarian detioration, no secondary sex characteristics

Question 22

Things that contribute to increased frequency of a disorder in a specific population

Answer 22

Founder Effect- when a few individuals migrate and find a new isolated, different population

Genetic Drift- higher or lower frequency transmission of particular gene, particularly impactful with smaller populations

Inbreeding

Heterozygote advantage

Question 23

Neurofibromatosis I

Answer 23

Autosomal Dominant/haploinsufficiency, 50% cases arise from de novo mutations
Diagnostic Criteria- 6 or more cafe au lait spots, 2 or more neurofibromas (composed of schwann cells, nerve fibers, fibroblasts), first degree relative with nf-1, optic pathway tumor, poor coordination, learning disabilities
NF-1 downregulates Ras oncogene

Question 24

Target vs Signal Amplication

Examples and Characteristics

Answer 24

Target- PCR, RT-PCR, Gel
Greater analytical sensitivty, lower limit of detection, high risk of contamination and false positives
Signal- Branched, Hybrid Capture, Invader technology

Question 25

Methods of detecting novel sequence variation
Sanger Sequency

NGS

Answer 25

Dideoxy NTP’s, chain termination
Limitations: allelic ambiguity, only sequences coding and splice sites, cannot detect low-level mosaicism, not quantitative

Massive amount of sequence data, Quantitative, Can detect rare events, no cis vs. trans ambiguity
Complex, still requires target enrichment and requires software

Question 26

Relative Risk

Answer 26

Prevalence among relatives of affected/Prevalence in the population

Question 27

Gene Therapy Mechanisms (4)

Answer 27

Gene augmentation therapy, directly alter/repair the mutated gene, provides gene that adds missing funtions or regulates the expression of another gene, use to silence or inhibit genes