Step 1 First Aid – Genetics – Flashcards

Codominance

Variable expression

Incomplete penetrance BRCA1

Imprinting

Anticipation

Loss of heterozygosity

Dominant negative mutation

Linkage disequilibrium HLA alleles

Mosaicism

Locus heterogeneity

Heteroplasmy

Uniparental disomy

If a population is in H-W equilibrium and p and q are separate alleles, then: Dz prevalence: p^2 + 2pq + q^2 = 1 Allele prevalence: p + q = 1 2pq = heterozygote prevalence Prevalence of XR dz in males = q and in females = q^2

p + q = 1

2pq

q

q^2

1.) No mutation at the locus 2.) No selection for any genotypes at the locus 3.) Completely random mating 4.) No migration

At a single locus, only 1 allele is active; the other is inactive (imprinted/inactivated by methylation). Deletion of the active allele --> dz. Most common example: Prader-Willi and Angelman's syndromes

Both syndromes due to inactivation or deletion of genes on chromosome 15. Can also occur as a result of uniparental disomy.

Deletion of *P*aternal allele. Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia.

Deletion of M aternal allele. Mental retardation, seizures, ataxia, inappropriate laughter ("happy puppet").

Autosomal dominant. Often due to defects in structural genes. Many generations, both male and female, affected. Often pleiotropic and, in many cases, present clinically after puberty. Family Hx crucial to Dx.

Autosomal recessive 25% of offspring from 2 carrier parents are affected. Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe than dominant d/o's; pts often present in childhood.

X-linked recessive. Sons of heterozygous mothers have a 50% chancce of being affected. No male-to-male transmission. Commonly more severe in males. Heterozygous females may be affected.

X-linked dominant. Transmitted thru both parents. Either male or female offspring of the affected mother may be affected, while *ALL female* offspring of the *affected father* are diseased.

(Archtypical example of X-linked dominant dz) Formerly known as vitamin D-resistant rickets. Inherited d/o resulting in incr phosphate wasting at proximal tubule. Results in rickets-like presentation.

Mitochondrial inheritance. Transmitted only thru mother. All offspring of affected females may show signs of dz. Variable expression in population due to heteroplasmy.

(mitochondrial inheritance dz's) Degeneration of retinal ganglion cells and axons. Leads to acute loss of central vision.

Cell-signaling defect of fibroblasts growth factor (FGF) receptor 3. Results in dwarfism; short limbs, but head and trunk are normal size. Associated w/ advanced paternal age.

Formerly known as adult polycystic kidney dz. Always bilateral , massive enlargement of kidneys due to multiple large cysts. Pts p/w flank pain, hemature, HTN, progressive renal failure. 90% cases are due to a mutation in APKD1 (chromosome 16 ; 16 letters in "polycystic kidney"). Associated w/ polycystic liver dz, berry aneurysms, mitral valve prolapse. Infantile form is recessive.

Colon becomes covered w/ adenomatous polyps after puberty. Progresses to colon cancer unless resected. Deletion on chromosome 5 (APC gene ); 5 letters in "polyp".

Elevated LDL due to defective or absent LDL receptor. Heterozygotes (1:500) have cholesterol ~300 mg/dL. Homozygotes (very rare) have cholesterol ~700+ mg/dL, severe athersclerotic dz early in life, and tendon xanthomas (clasically in the Achilles tendon); MI may develop before age 20.

Inherited d/o of blood vessels. Findings: telangiectasia, recurrent epistaxis, skin discolorations, arteriovenous malformations (AVMs).

Spheroid erythrocytes due to spectrin or ankyrin defect; hemolytic anemia; Incr MCHC. Splenectomy is curative.

Findings: depression, progressive dementia, choreiform mvmts, caudate atrophy, and decr levels of GABA and ACh in the brain. Sx manifest in affected indvls btw the ages of 20-50. Gene located on Chr 4 ; trinucleotide repeat d/o: (CAG) ("Hunting 4 food")

Fibrillin gene mutation --< connective tissue d/o affecting skeleton, heart, and eyes. Findings: tall w/ long extremities, pectus excavatum, hyperextensive joints, and long, tapering fingers and toes (arachnodactyly, below); cystic medial necrosis of aorta --< aortic incompetence and dissecting aortic aneurysms; floppy mitral valve. Subluxation of the lenses.

Several distinct syndromes (I, II, III) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, thyroid, and adrenal medula. Men II and III associated w/ ret gene.

Findings: café-au-lait spots, neural tumors, Lisch nodules (pigmented iris hamartomas). Also marked by skeletal d/o's (e.g., scoliosis), optic pathway gliomas, pheochromocytoma, and incr tumor susceptibility. On long arm of chromosome 17 ; 17 letters in "von Recklinghausen"

Bilateral acoustic neuroma, juvenile cataracts. NF2 gene on chromosome 2 ; (type 2 = 22 )

Findings: facial lesions (adenoma sebaceum) hypopigmented "ash leaf spots" on skin cortical and retinal hamartomas seizures mental retardation renal cysts and renal angiomyolipomas cardiac rhabdomyomas incr incidence of astrocytomas. Incomplete penetrance, variable presentation.

Findings: Hemangioblastomas of retina/cerebellum/medulla about 1/2 of affected indvls develop multiple bilateral renal cell carcinomas and other tumors. Associated w/ deletion of VHL gene (tumor suppressor) on chromosome 3 (3p). Results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors. Von Hippel-Linau = 3 words for chromosome 3.

Albinism ARPKD (formerly known as infantile polycystic kidney dz) Cystic fibrosis Glycogen storage dz's Hemochromatosis Mucopolysaccharidoses (except Hunter's) Phenylketonuria Sickle cell anemias Sphingolipidoses (except Fabry's) Thalassemias

Autosomal-recessive defect in CFTR gene on chromosome 7, commonly deletion of Phe 508. CFTR channel actively secretes Cl- into lungs and GI tract, and actively reabsorbs Cl- from sweat. *Most common lethal genetic dz of Caucasians

Secretion of abnormally thick mucus that plugs lungs, pancreas and liver | Recurrent pulmonary infxns (Pseudomonas species and S. aures), chronic bronchitis, bronchiectasis, pancreatic insufficiency (malabsorption and steatorrhea), meconium ileus in newborns.

Infertility in males due to bilateral absence of vas deferens. Fat-soluble vitamin deficiencies (A, D, E, K). Can present as failure to thrive in infancy.

Incr concentration of Cl- ions in sweat test.

N-acetylcysteine to loosen mucous plugs (cleaves disulfide bonds w/in mucous glycoproteins).

B ruton's agammaglobulinemia W iskott-Aldrich syndrome F ragile X G 6PD deficiency O cular albinism L esch-Nyhan syndrome D uchenne's (and Becker's) muscular dystrophy H emophilia A and B F abry's dz H unter's syndrome "B e W ise, F ool's GOLD H eeds F alse H ope" Female carriers are rarely affected due to random inactivation of X chromosomes in each cell.

X-linked frame-shift mutation --< deletion of dystrophin gene --< accelerated muscle breakdown. Weakness begins in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscles due to fibrofatty replacement of muscle; cardiac myopathy. Use of Gowers' maneuver, requiring assistance of the upper extremities to stand up, is characteristic. Onset before 5 yrs of age. D uchenne's = D eleted D ystrophin.

X-linked mutated dystrophin gene. Less severe than Duchenne's. Onset in adolescence or early adulthood.

(associated w/ Duchenne's and Becker's muscular dystrophies) The longest known human gene --< incr rate of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle.

Incr CPK and muscle biopsy.

X-linked defect affeccting the methylation and expression of the FMR1 gene. Associated w/ chromosomal breakage. The 2nd most common cause of genetic mental retardation (after Down syndrome). Trinucleotide repeat disorder (CGG)

Macro-orchidism (enlarged testes), long face w/ a large jaw, large everted ears, autism. "Fragile X = eX tra-large testes, jaw, ears."

Hunting ton's dz, my otonnic dystrophy, Fried rich's ataxia, fragile X syndrome. ("Try [tri nucleotide] hunting for my fried eggs [X ]") Huntington's = CAG MyoT onic dystrophy = CT G FraG ile X syndrome = CG G Friedreich's ataxia = GAA May show genetic anticipation (dz severity incr and age of onset decr in successive generations; germline expansion in females)

1:700 Most common chromosomal d/o and most common cause of congenital mental retardation.

Mental retardation, flat facies , prominent epicanthal folds , simian crease [below], gap btw 1st 2 toes, duodenal atresia, congenital hear dz (most commonly septum primum-type ASD). Assoc w/ incr risk of ALL and Alzheimer's dz (< 35 yrs of age)

Due to meiotic nondisjunction of homogous chromosomes (associated w/ advancced maternal age; from 1:1500 in women >20 to 1:25 in women <45)

Can occur in anaphase I: Or in anaphase II:

Genetic cause in 4% of cases? Due to robertsonian translocation.

Due to Down mosaicism (no maternal association)

Decr alpha-fetoprotein Incr Beta-hCG Decr estriol Incr Inhibin A Ultrasound shows nuchal translucency.

1:8000 Most common trisomy resulting in live birth after Down syndrome.

Severe mental retardation Rocker-bottom feet micrognathia (small jaw) Low-set ears Clenched hands Prominent occiput Congenital heart dz Death usually occurs w/in 1 yr of birth.

1:15,000

Severe mental retardation Rocker-bottom feet Microphthalmia Microcephaly Cleft lip/palate holoProsencephaly Polydactyly Congenital heart dz Death usually occurs w/in 1 yr of birth.

Nonreciprocal chromosomal transloccation that commonly involves chromosome pairs 13, 14, 15, 21, and 22. One of the most common types of translocation. Occurs when the long arms of two acrocentric chromosomes (chromosomes w/ the centromeres near the ends) fuse at the centromere and the 2 short arms are lost.

Balanced translocations normally do not cause any abnormal phenotype. Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (e.g., Down syndrome, Patau's syndrome).

Chromosome rearrangement in which a segment of a chromosome is reveresed end-to-end. May result in decr fertility.

Pericentric: Involves centromere; proceeds thru meiosis. Paracentric: does not involve centromere; does not proceed thru meiosis.

Congenital microdeletion of short arm of Chr 5 (46,XX or XY,5p-)

Microcephaly Moderate to severe mental retardation High-pitched crying/mewing (Cri-du-chat = "cry of the cat") Epicanthal folds Cardiac abnormalities

Congenital microdeletion of long arm of Chr 7 (deleted region includes elastin gene).

Distinctive "elfin" facies Mental retardation Well-developed verbal skills Cheerful disposition Extreme friendliness w/ strangers Cardiovascular problems

Variable presentation, including: C left palate A bnormal facies T hymic aplasia --< T-cell deficiency C ardiac defects H ypocalcemia secondary to parathyroid aplasia Due to microdeletion at chromosome 22 q11. "CATCH-22 "

Due to aberrat development of 3rd and 4th branchial pouches

DiGeorge syndrome: thymic, parathyroid, and cardiac defects. Velocardiofacial syndrome: palate, facial, and cardiac defects.