Genetics

Question 1

Variable expressivity

Answer 1

Differences in severity of AD disorders (e.g. a patient w/ Marfan may have only tall stature, while another pt w/ Marfan will have tall stature + aortic root dilation, lens dislocation, etc)

Question 2

Anticipation

Answer 2

Increased severity or earlier onset in successive generations; commonly seen in trinucleotide repeat disorders (Huntingon’s disease, myotonic dystrophy, Fragile X, Friedreich ataxia [spinocerebellar degeneration/spinal ataxia])

Question 3

Incomplete penetrance and risk of expressing a phenotype (equation)

Answer 3

Not all individuals with a mutant genotype show the mutant phenotype. (% Penetrance) * (Probability of inheriting genotype) = Risk of expressing phenotype

Question 4

Mosaicism

Answer 4

Presence of 2+ cell lines, each with a unique nuclear genome (genotype), within the same person. E.g. mild Turner (due to 45X/46XX somatic mosaicism), Klinefelter, Down’s

Question 5

Somatic vs. Germline Mosaicism

Answer 5

Somatic: mutation arises from mitotic errors after fertilization and propagates thru multiple tissues/organs; mutation affects cells forming the body causing disease manifestations to develop in affected individuals

Germline: Mutation only in egg or sperm cells; allows affected genes to pass to offspring. If parents & relatives unaffected, suspect gonadal (germline) mosaicism

If a mitotic error occurs very early in embryogenesis, before separation of the germline, a pt could have both somatic and germline mosaicism

Question 6

Uniparental disomy

Answer 6

Both members of a chromosomal pair are inherited from one parent, causing probs due to genetic imprinting (selective inactivation of paternal or maternal alleles). Most often d/t chromosomal deletions; can cause Prader-Willi or Angelman’s syndromes

Question 7

Imprinting

Answer 7

Caused by DNA methylation (attaching methyl groups to cytosine residues in the DNA molecule to silence genes). Methylation occurs at CpG islands (cytosine-guanine dinucleotide repeats)

Question 8

Heteroplasmy

Answer 8

Coexistence of distinct versions of mitochondrial genomes in an individual cell. mtDNA is passed from mother to all her children. Seen as variable expression of a mitochondrial disease (e.g. mitochondrial myopathy) among all affected members in a family. Severity of mito disease often related to proportion of abnormal to normal mitochondria

Question 9

Pleiotropy

Answer 9

Occurrence of multiple phenotypic manifestations, often in diff organ systems, resulting from a single gene mutation

Question 10

Loss of heterozygosity

Answer 10

If a parent develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes.

E.g. two hit hypothesis (Rb), Lynch syndrome (HNPCC), Li Fraumeni syndrome

Question 11

Genetic linkage

Answer 11

Tendency of alleles located near ach other on same chromosome to be inherited jointly

Question 12

Linkage disequilibrium

Answer 12

2 allele loci are said to be in linkage disequilibrium when a pair of alleles are inherited together in the same gamete (haplotype) more or less often than would be expected given random pairing. Most often occurs when the genes are in close physical proximity on same chromosome

E.g. if frequency of allele A is 0.2 and of allele B is 0.3, the expected frequency of them being inherited together would be 0.2*0.3 = 0.06. But if the observed frequency is > 0.06, the population is said to be in linking disequilibrium

Question 13

Dominant negative mutations

Answer 13

Occur when abnormal gene negatively affects product of the wild-type gene in the same cell. E.g. Certain p53 mutations can lead to translation of a protein product that prevents wt p53 from binding the promoter of its target genes.

Question 14

Locus heterogeneity

Answer 14

Ability of one disease or trait to be caused by mutations in multiple diff genes (e.g. familial hypercholesteremia can be d/t mutations in LDL receptor, apoB100, etc)

Question 15

Heteroplasmy

Answer 15

Coexistence of distinct versions of mitochondrial genomes in an individual cell. mtDNA is passed from mother to all her children. Seen as variable expression of a mitochondrial disease (e.g. mitochondrial myopathy) among all affected members in a family. Severity of disease often related to proportion of abnormal to normal mitochondria

Question 16

Hardy-Weinberg equations

Answer 16

p^2 + 2pq + q^2 = 1
p + q = 1

p^2 = freq of homozygosity for allele A, q^2 = freq of homozygosity for allele a (prevalence), 2pq = freq of heterozygosity (carrier frequency, if AR disorder)

For X-linked R disease, frequency in males = q, females = q^2, carrier state for females = 2q

Question 17

Common polygenic disorders

Answer 17

"ITS His AGE"
Ischemic heart disease
Type II DM
Schizophrenia
Hypertension
Androgenic alopecia
Glaucoma
Epilepsy

Question 18

Fanconi syndrome vs. Fanconi anemia

Answer 18

Fanconi syndrome: generalized reabsorption defect in PCT –> increased excretion of AAs, glc, bicarb, phosphate. Can be d/t hereditary defects, ischemia, MM, drugs (e.g. expired tetracyclines), lead poisoning. Can cause metabolic acidosis, hypophosphatemia, osteopenia

Fanconi anemia: DNA repair defect causing BM failure, short stature, increased tumor/leukemia risk, cafe au lait spots, thumb defects.

Question 19

Tuberous sclerosis characteristics

Answer 19

HAMARTOMAS:
Hamartomas in CNS & skin
Angiofibromas
Mitral regurg
Ash-leaf spots
cardiac Rhabdomyoma
(Tuberous sclerosis)
autosomal dOminant
Mental retardation
Angiomyolipoma
Seizures, Shagreen patches

Question 20

Epistasis

Answer 20

Interactions btwn many genes combine to create a new phenotype or mask/modify the phenotype of one of the genes (e.g. pts w/ SSA who have a mutation causing persistence of high HbF levels will have less severe clinical course)

Question 21

Edwards vs. Patau syndrome

Answer 21

Edward: tri 18, PRINCE Edward = Prominent occiput, Rocker bottom feet, Intellectual disability, Nondisjunxn, Clenched fists w/ overlapping fingers (hypertonia), low-set Ears. Also micrognathia, congenital heart/GI/renal disease. Death by 1 yo

Patau: tri 13; holoProsencephaly, cutis aPlasia, cleft liP/Palate, Polydactyly, Polycystic kidney dz. Also GI anomalies (omphalocele, umbilical hernia), midline facial defects