question

What is codominance?

answer

DEFINITION both alleles contribute to the phenotype of the heterozygote EXAMPLE blood groups A, B, and AB

question

What is variable expressivity?

answer

DEFINITION phenotype varies among individuals with same genotype EXAMPLE two patients with NF1 may have varying disease severity

question

What is incomplete penetrance?

answer

DEFINITION not all individuals with a mutant genotype show the mutant phenotype EXAMPLE BRCA1 gene mutations do not always result in breast or ovarian cancer

question

What is pleiotropy?

answer

DEFINITION one gene contributes to multiple phenotypic effects EXAMPLE PKU causes mental retardation and hair/skin changes

question

What is imprinting?

answer

DEFINITION difference in gene expression depend on whether the mutation is of maternal or paternal origin EXAMPLE Prader-Willi and Angelman

question

What is anticipation?

answer

DEFINITION increased severity or earlier onset of disease in succeeding generations EXAMPLE Huntington

question

What is meant by loss of heterozygosity and of what genes is it not true?

answer

DEFINITION if a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops NOT TRUE IN oncogenes EXAMPLE retinoblastoma and the "two-hit" hypothesis

question

What is a dominant negative mutation?

answer

DEFINITION a single mutation exerts a dominant effect; a heterozygote produces a nonfunctional altered protein that also prevents the normal gene from functioning EXAMPLE mutation of a transcription factor in its allosteric site can still bind DNA, preventing the wild-type from binding

question

What is linkage disequilibrium?

answer

tendency for certain alleles at two linked loci to occur together more often than expected by change; measured in a population, not in a family; often varies in different populations

question

What is mosaicism?

answer

DEFINITION cells in the body differ in genetic makeup due to postfertilization loss or change of genetic information during mitosis; can be germ-line (gonadal mosaicism), which may produce disease that is not carried by parents' somatic cells EXAMPLE mutation in the embryonic precursor of the bone marrow stem cells --> hematologic mosaic individual; fusion of two zygotes --> chimera

question

What is locus heterogeneity?

answer

DEFINITION mutations at different loci produce the same phenotype EXAMPLE Marfan's, MEN2b, and homocystinuria all cause marfanoid habitus; albinism

question

What is heteroplasmy?

answer

presence of both normal and mutated mtDNA --> variable expression in mitochondrial inherited disease

question

What is uniparental disomy? What are its types?

answer

DEFINITION offspring receives two copies of a chromosome from one parent and no copies from the other TYPES heterodisomy (meiosis I error), isodisomy (meiosis II error or postzygotic chromosomal duplication of one pair and loss of the other pair) EXAMPLES child manifests recessive disorder when only one parent is a carrier; note that most occurrences of uniparental disomy result in a normal phenotype as the process is euploid, not aneuploid

question

What are the assumptions of Hardy-Weinberg population genetics?

answer

1. no mutation at the locus 2. no selection for any of the genotypes at the locus 3. completely random mating 4. no net migration

question

What calculations are associated with Hardy-Weinberg population genetics?

answer

population in equilibrium displays p2 + 2pq + q2 = 1 and p + q = 1, where p2 = frequency of homozygosity for allele p q2 = frequency of homozygosity for allele q 2pq = frequency of heterozygosity (carrier frequency, if autosomal recessive) NOTE in an X-linked recessive disease, the frequency in males is equal to q and the frequency in females is equal to q2

question

What is imprinting?

answer

DEFINITION at some loci, only one allele is active, and the other is inactive by methylation; deletion of active allele --> disease EXAMPLE Prader-Willi and Angelman (inactivation or deletion of genes on chromosome 15); can also occur as a result of uniparental disomy

question

What is Prader-Willi syndrome?

answer

CAUSE paternal copy of allele on chromosome 15 not expressed PRESENTATION mental retardation, hyperphagia, obesity, hypogonadism, hypotonia --Prader-willi is Paternal.--

question

What is Angelman's syndrome?

answer

CAUSE maternal copy of allele on chromosome 15 is not expressed PRESENTATION mental retardation, seizures, ataxia, inappropriate laughter --angelMan's is Maternal.--

question

Which mode of inheritance is often pleiotropic?

answer

autosomal dominant

question

Which mode of inheritance normally confers diseases of enzyme deficiencies?

answer

autosomal recessive

question

Which mode of inheritance does not show male-to-male transmission?

answer

X-linked recessive

question

Hypophosphatemic rickets is inherited in what pattern?

answer

X-linked dominant

question

For a female to be affected by an X-linked recessive disease, what must their allele distribution be?

answer

homozygous

question

If all female offspring of an affected father are affected by a disease, what is its inheritance pattern?

answer

X-linked dominant

question

If all offspring of an affected mother are affected by a disease, what is its inheritance pattern?

answer

mitochondrial

question

Which mode of inheritance shows variable expression due to heteroplasmy?

answer

mitochondrial

question

Diseases of which inheritance pattern present with myopathy, CNS disease, and "ragged red fibers?"

answer

mitochondrial

question

In which mode of inheritance do sons of heterozygous mothers have a 50% chance of being affected?

answer

X-linked recessive

question

Name the mode of inheritance. Achondroplasia

answer

autosomal dominant

question

Name the mode of inheritance. ARPKD

answer

autosomal recessive

question

Name the mode of inheritance. Bruton's agammaglobulinemia

answer

X-linked recessive

question

Name the mode of inheritance. Tuberous sclerosis

answer

autosomal dominant

question

Name the mode of inheritance. von Hippel-Lindau disease

answer

autosomal dominant

question

Name the mode of inheritance. Duchenne's muscular dystrophy

answer

X-linked recessive

question

Name the mode of inheritance. Wiskott-Aldrich syndrome

answer

X-linked recessive

question

Name the mode of inheritance. cystic fibrosis

answer

autosomal recessive

question

Name the mode of inheritance. MEN (multiple endocrine neoplasias)

answer

autosomal dominant

question

Name the mode of inheritance. hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

answer

autosomal dominant

question

Name the mode of inheritance. albinism

answer

autosomal recessive

question

Name the mode of inheritance. Fabry's disease

answer

X-linked recessive

question

Name the mode of inheritance. Becker's muscular dystrophy

answer

X-linked recessive

question

Name the mode of inheritance. phenylketonuria

answer

autosomal recessive

question

Name the mode of inheritance. thalassemias

answer

autosomal recessive

question

Name the mode of inheritance. hereditary spherocytosis

answer

autosomal dominant

question

Name the mode of inheritance. Huntington's disease

answer

autosomal dominant, expresses anticipation

question

Name the mode of inheritance. Marfan's syndrome

answer

autosomal dominant

question

Name the mode of inheritance. glycogen storage diseases

answer

autosomal recessive

question

Name the mode of inheritance. FAP (familial adenomatous polyposis)

answer

autosomal dominant

question

Name the mode of inheritance. ADPKD

answer

autosomal dominant

question

Name the mode of inheritance. familial hypercholesterolemia (hyperlipidemia type IIA)

answer

autosomal dominant

question

Name the mode of inheritance. hemochromatosis

answer

autosomal recessive

question

Name the mode of inheritance. neurofibromatosis, types I and II

answer

autosomal dominant

question

Name the mode of inheritance. Lesch-Nyhan

answer

X-linked recessive

question

Name the mode of inheritance. ocular albinism

answer

X-linked recessive

question

Name the mode of inheritance. hemophilia A and B

answer

X-linked recessive

question

Name the mode of inheritance. mucopolysaccharidoses (except Hunter's)

answer

autosomal recessive

question

Name the mode of inheritance. G6PD deficiency

answer

X-linked recessive

question

Name the mode of inheritance. sphingolipidoses (except Fabry's)

answer

autosomal recessive

question

Name the mode of inheritance. ornithine transcarbamoylase deficiency

answer

X-linked recessive

question

Name the mode of inheritance. sickle cell anemia

answer

autosomal recessive

question

Name the mode of inheritance. Hunter's syndrome

answer

X-linked recessive

question

Name the X-linked recessive disorders.

answer

Bruton's agammaglobulinemia Wiskott-Aldrich syndrome Fabry's disease G6PD deficiency Ocular albinism Lesch-Nyhan syndrome Duchenne's (and Becker's) muscular dystrophy Hunter's Syndrome Hemophilia A and B Ornithine transcarbamoylase deficiency --Be Wise, Fool's GOLD Heeds Silly HOpe.--

question

What is the pathogenesis of achondroplasia? With what is it associated?

answer

PATHOGENESIS cell-signaling defect of FGF receptor 3 --> dwarfism, short limbs, larger head with normal trunk size ASSOCIATIONS advanced paternal age

question

What is the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD)? What are its possible associated complications?

answer

PATHOGENESIS 85% of cases due to mutation in PKD1 on chromosome 16 --> formation of multiple large cysts --> bilateral, massive enlargement of kidneys --> flank pain, hematuria, HTN, progressive renal failure COMPLICATIONS polycystic liver disease; berry aneurysms --> subarachnoid hemorrhage; mitral valve prolapse

question

What disease is conferred by a mutation of PKD1 on chromosome 16?

answer

ADPKD

question

What is the pathogenesis of FAP?

answer

mutation in APC gene on chromosome 5 --> hundreds to thousands of adenomatous polys on colon after puberty --> colon cancer

question

APC mutations are associated with what disease?

answer

FAP

question

What is the pathogenesis of familial hypercholesterolemia (hyperlipidemia type IIA)?

answer

absent or defective LDL receptor --> elevated LDL (heterozygotes, cholesterol ~300; homozygotes, cholesterol >700) --> severe atherosclerotic disease early in life, tendon xanthomas, MI

question

In familial hypercholesterlemia (hyperlipidemia type IIA), where do tendon xanthomas classically appear?

answer

Achilles

question

What is the pathogenesis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)?

answer

autosomal dominant inherited disorder of blood vessels --> telangiectasia (skin and mucous membranes), recurrent epistaxis, arteriovenous malformations (AVMs), GI bleeding, hematuria

question

What is the pathogenesis and treatment of hereditary spherocytosis?

answer

PATHOGENESIS defect in spectrin or ankyrin --> spheroid erythrocytes --> hemolytic anemia, increased MCHC TREATMENT splenectomy

question

What is the pathogenesis of Huntington's disease?

answer

trinucleotide repeat disorder of (CAG)n --> decreased levels of GABA and ACh in brain --> depression, progressive dementia, choreiform movements, caudate atrophy

question

On which chromosome is the gene responsible for Huntington's located?

answer

chromosome 4 --Hunting 4 food.--

question

What is the pathogenesis of Marfan's syndrome?

answer

mutation in fibrillin-1 --> connective tissue disorder affecting skeleton, heart, and eyes --> tall with long extremities, pectus excavatum, hypermobile joints, arachnodactyly (long and tapering fingers and toes); floppy mitral valve; subluxation of lenses cystic medial necrosis of aorta --> aortic incompetence, dissecting aortic aneurysms

question

What is the presentation of MEN (multiple endocrine neoplasias)?

answer

familial tumors of endocrine glands (pancreas, parathyroid, pituitary, thyroid, adrenal medulla) NOTE types include 1, 2A and 2B; both 2A and 2B are associated with the ret gene

question

Which disease is associated with the ret gene?

answer

MEN 2A and 2B

question

Which disease is associated with chromosome 17?

answer

neurofibromatosis type 1 (the gene codes for neurofibromatin)

question

Which disease is associated with the NF2 gene on chromosome 22?

answer

neurofibromatosis type 2 (this gene codes for merlin)

question

What is the presentation of neurofibromatosis type I (von Recklinghausen's disease)?

answer

cafe-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas) skeletal disorders (scoliosis) and optic pathway gliomas

question

What is the presentation of neurofibromatosis type II?

answer

bilateral acoustic schwannomas juvenile cataracts

question

What are the findings in tuberous sclerosis?

answer

facial lesions (adenoma sebaceum) hypopigmented "ash leaf spots" on skin cortical and retinal hamartomas seizures mental retardation renal cysts renal angiomyolipomas cardiab rhabdomyomas increased incidence of astrocytomas

question

Which of the following does tuberous sclerosis show? incomplete penetrance anticipation variable presentation heteroplasmy codominance dominant negative mutation

answer

incomplete penetrance with variable presentation

question

What is the pathogenesis of von Hippel-Lindau disease?

answer

deletion of VHL gene (tumor suppressor) on chromosome 3 (3p) --> constitutive expression of HIF (transcription factor), activation of angiogenic growth factors --> hemangioblastomas of retina/cerebellum/medulla; multiple bilateral renal cell carcinomas and other tumors (including pheochromocytomas and ependymomas)

question

Which autosomal dominant disorder confers an increased risk for renal cell carinoma?

answer

von Hippel-Lindau disease

question

What is the most common lethal genetic disease of the white population?

answer

CF

question

Which autosomal dominant disorder confers an increased risk for MI at age 20?

answer

familial hypercholesterolemia (hyperlipidemia type IIA)

question

What is the pathogenesis of cystic fibrosis?

answer

autosomal recessive defect in CFTR gene on chromosome 7 (deltaP508) --> abnormal protein folding --> degradation of Cl- channel before reaching cell surface --> decreased secretion of Cl- into lungs and GI tract, decreased absorption of Cl- from sweat --> secretion of abnormally thick mucus --> development of mucus plugs in pancreas, liver, and lungs --> recurrent pulmonary infections (most commonly Psuedomonas aeruginosa, S. aureus, H. influenzae); chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption syndrome causing steatorrhea and fat soluble vitamin deficiency); nasal polyps; meconium ileus in newborns; failure to thrive in infancy ALSO bilateral absence of vas deference in males --> infertility

question

I say "meconium ileus," you say...?

answer

cystic fibrosis

question

Infection by what agent is the most common cause of death in CF patients?

answer

P. aeruginosa

question

What is the treatment for CF and what is its mechanism of action?

answer

DRUG N-acetylcysteine/mucormyst MOA cleavage of disulfide bonds within mucus glycoproteins --> loosening of mucus plugs

question

What is the diagnostic test for CF?

answer

increased concentration of Cl- ions in sweat test

question

Why are females with X-linked recessive disorders likely to have less severe symptoms?

answer

random X chromosome inactivation in each cell (formation of Barr bodies)

question

What is the pathogenesis of Duchenne's muscular dystrophy?

answer

X-linekd FRAMESHIFT mutation --> deletion of dystrophin gene (DMD) --> accelerated muscle breakdown --> weakness in pelvic girdle muscles, progressing superiorly; fibrofatty replacement of muscle --> pseudohypertrophy of calf muscles; cardiac myopathy

question

What is the longest known human gene?

answer

DMD, coding for dystrophin Because it is so long, there is an increased rate of spontaneous mutation; this is why there are so many possible mutations causing Duchenne's muscular dystrophy

question

What is Gowers' maneuver, and of what is it indicative?

answer

DEFINITION individual, usually a boy <5, uses upper extremities to stand up DISEASE Duchenne's muscular dystrophy

question

What is the function of dystrophin?

answer

anchoring of muscle fibers, primarily cardiac and skeletal

question

What is Becker's muscular dystrophy?

answer

a less severe type of Duchenne's muscular dystrophy; onset in adolescence or early adulthood

question

What is the most common cause of mental retardation?

answer

Down syndrome

question

What is the second most common cause of mental retardation?

answer

Fragile X syndrome

question

What is the pathogenesis of Fragile X syndrome?

answer

X-linked trinucleotide repeat disorder (CGG)n --> defect in methylation and expression of FMR1 gene --> macroorchidism (enlarged testes), long face with large jaw; large everted ears; autism; mitral valve prolapse --fragile X =eXtra large testes, jaw, ears--

question

Name the trinucleotide repeat expansion diseases.

answer

HUNTINGton's myotonic dystrophy FRIEDreich's ataxia fragile X --TRI HUNTING for MY FRIED eggs (x)--

question

For each trinucleotide repeat expansion disease, name the trinucleotide involved.

answer

fragile X: (cGg)n Friedreich's ataxia: (gAa)n Huntington's: (cAg)n MYotonic dystrophy: (cTg)n --X-Girlfriend's First Aid Helped Ace MY Test.--

question

Which of the following are trinucelotide repeat expansion diseases likely to show? incomplete penetrance anticipation variable presentation heteroplasmy codominance dominant negative mutation

answer

anticipation

question

What are the three autosomal trisomies not fatal in utero?

answer

Down (trisomy 21) Edwards' (trisomy 18) Patau's (trisomy 13) --Drinking age, Election age, Puberty age.--

question

What is the genetic cause of the majority of Down cases? And the remainder?

answer

95% due to meiotic nondisjunction of homologous chromosomes, associated with advanced maternal age (1:25 in women >45 but only 1:1500 in women <20) 4% due to Robertsonian translocation 1% due to Down mosaicism (no maternal association)

question

What are the findings in Down syndrome? What is the life expectancy?

answer

mental retardation flat facies prominent epicanthal folds simian crease gap between first two toes duodenal atresia congenital heart disease (ostium primum type ASD most common) increased risk of ALL and Alzheimer's (>35 years of age) LIFE EXPECTANCY 45 years

question

What test can be given in pregnancy to diagnose Down syndrome?

answer

PREGNANCY QUAD SCREEN decreased alpha-fetoprotein, increased beta-hCG, decreased estriol, increased inhibin A ULTRASOUND IN FIRST TRIMESTER increased nuchal translucency

question

What are the findings in Edwards' syndrome? What is the life expectancy?

answer

severe mental retardation rocker-bottom feet micrognathia (small jaw) LOW-SET EARS clenched hands prominent occiput congenital heart disease LIFE EXPECTANCY 1 year

question

What are the results of the pregnancy quad screen in Edwards' syndrome?

answer

decreased alpha-fetoprotein decreased beta-hCG decreased estriol normal inhibin A

question

What are the findings in Patau's syndrome?

answer

severe mental retardation rocker-bottom feet microphtalmia microcephaly CLEFT LIP/PALATE HOLOPROSENCEPHALY polydactyly congenital heart disease LIFE EXPECTANCY 1 year max

question

What are the results of the first-trimester pregnancy screen in Patau's syndrome?

answer

decreased free beta-hCG decreased PAPP-A increased nuchal translucency

question

Name the trisomy: decreased free beta-hCG decreased PAPP-A increased nuchal translucency

answer

Patau's

question

Name the trisomy: decreased alpha-fetoprotein increased beta-hCG decreased estriol increased inhibin A

answer

Down

question

Name the trisomy: decreased alpha-fetoprotein decreased beta-hCG decreased estriol normal inhibin A

answer

Edwards'

question

What is the incidence rate for the three autosomal trisomies not fatal in utero?

answer

DOWN 1:700 EDWARDS' 1:8000 PATAU'S 1:15000

question

What is a Robertsonian translocation?

answer

nonreciprocal chromosomal translocation commonly involving chromosome pairs 13, 14, 15, 21, and 22; one of the most common types of translocation; occurs when the long arms of 2 acrocentric chromosomes fuse at the centromere and the two short arms are lost

question

What is an acrocentric chromosome?

answer

chromosome with centromere near the end, thus having very short arms

question

When are Robertsonian translocations of clinical significance?

answer

when they are unbalanced; these cause miscarriage, stillbirth, and chromosomal imbalance

question

What is the genetic basis for cri-du-chat syndrome?

answer

congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p--)

question

What are the findings in cri-du-chat syndrome?

answer

microcephaly moderate to severe mental retardation high-pitched crying or mewing epicanthal folds cardiac abnormalities (most often VSD)

question

What is the genetic basis of Williams syndrome?

answer

congenital microdeletion of long arm of chromosome 7, deletion include elastin gene

question

What is the presentation of Williams syndrome?

answer

distinctive "elfin" facies intellectual disability hypercalcemia (increased sensitivity to vitamin D) well-developed verbal skills ("5 favorite animals" will include made-up animals, dinosaurs, etc) extreme friendliness with strangers cardiovascular problems NOTE modern research is disproving some of the above. For your own information (though the above is likely to be tested on Step): http://www.ncbi.nlm.nih.gov/pubmed/1133652

question

What are the two 22q11 deletion syndromes?

answer

DiGeorge syndrome (thymic, parathyroid, cardiac defects) velocardiofacial syndrome (palata, facial, cardiac defects)

question

What is the presentation (although variable) of 22q11 deletion syndromes?

answer

Cleft palate Abnormal facies Thymic aplasia --> T cell deficiency Cardiac defects Hypocalcemia secondary to parathyroid aplasia 22q11 --CATCH 22--

question

What branchial pouches are involved in 22q11 deletion syndromes?

answer

3rd and 4th

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