Genetic Disorders

Mechanisms, patterns, and what happens when each one fails.

• Autosomal recessive disorders. Two carrier parents give each child a 1/4 chance of disease, 1/2 carrier, 1/4 unaffected non-carrier — unaffected siblings of a patient are 2/3 carriers (the exam's favorite denominator trick). The classics: cystic fibrosis (CFTR, ΔF508 most common — defective chloride channel, thick secretions, pancreatic insufficiency, elevated sweat chloride), sickle cell disease (β-globin Glu6Val — HbS polymerizes when deoxygenated), and hereditary hemochromatosis (HFE C282Y — iron overload with low penetrance, presenting in middle age with cirrhosis, diabetes, bronze skin).
• Autosomal dominant disorders. One affected parent → 50% risk per child; look for vertical transmission in the pedigree with male-to-male transmission (which excludes X-linkage). Marfan syndrome (FBN1/fibrillin-1 — tall, arachnodactyly, upward lens dislocation, aortic root dilation), neurofibromatosis type 1 (NF1/neurofibromin, a tumor suppressor — café-au-lait macules, axillary freckling, Lisch nodules, neurofibromas), Huntington disease, familial adenomatous polyposis (APC), and hereditary breast/ovarian cancer (BRCA1/2 — inherited dominantly even though the mechanism is loss of a tumor suppressor).
• X-linked recessive disorders. Affected males, carrier mothers, no male-to-male transmission; an affected father has carrier daughters and unaffected sons. Duchenne muscular dystrophy (dystrophin frameshift/deletion — proximal weakness by age 2-5, Gowers sign, calf pseudohypertrophy, markedly elevated CK; Becker is a milder in-frame mutation) and hemophilia A (factor VIII) and B (factor IX) — deep bleeds into joints and muscles with a prolonged PTT and normal PT.
• Trinucleotide repeats and anticipation. Huntington disease is a CAG repeat expansion in HTT: autosomal dominant chorea, psychiatric change, and dementia with onset usually 30s-40s, and caudate atrophy on imaging. Repeats expand across generations — anticipation: earlier and more severe disease in successive generations, most pronounced with paternal transmission in Huntington. Fragile X (CGG, FMR1) is the classic anticipation example on the X, where expansion occurs with maternal transmission.
• Chromosomal aneuploidies. Down syndrome (trisomy 21, ~95% from maternal meiotic nondisjunction, risk rising with maternal age): hypotonia, flat facies, single palmar crease, duodenal atresia, endocardial cushion (AV canal) defects, early Alzheimer disease, increased leukemia risk. Trisomy 18 (Edwards): clenched fists with overlapping fingers, rocker-bottom feet, micrognathia. Trisomy 13 (Patau): midline defects — cleft lip/palate, holoprosencephaly, polydactyly. Both 13 and 18 usually die within the first year.
• Sex chromosome disorders. Turner syndrome (45,X): short stature, streak ovaries with primary amenorrhea and infertility, webbed neck, broad chest, coarctation of the aorta and bicuspid aortic valve — the only viable monosomy. Klinefelter syndrome (47,XXY): tall, small firm testes, gynecomastia, infertility, diagnosed at puberty or in a fertility workup; testosterone low, FSH/LH high.
• Multifactorial inheritance. Many genes plus environment — neural tube defects, cleft lip/palate, congenital heart disease, type 2 diabetes, hypertension. No Mendelian ratio: recurrence risk is empiric (typically 2-5% for first-degree relatives), rises with more affected relatives and more severe disease, and drops sharply for more distant relatives. Folate before conception lowers neural tube defect recurrence — the actionable exam fact.
• Genetic testing and counseling principles. Counseling is non-directive: present risks and options, the patient decides. Testing a child for an adult-onset, unpreventable disease (Huntington) is deferred until the child can consent; testing for actionable childhood conditions is appropriate. Carrier screening (CF, hemoglobinopathies, Tay-Sachs in at-risk populations) targets reproductive planning. GINA protects against health-insurance and employment discrimination based on genetic results — but not life or disability insurance.

Each with the one fact that identifies it. Your course's slides are the authority; use this to check your list against.

1. 1Cystic fibrosis — ΔF508 in CFTR; thick secretions, pancreatic insufficiency, diagnosed by sweat chloride
2. 2CFTR — chloride channel misfolded and degraded in the most common ΔF508 mutation
3. 3Sickle cell disease — Glu6Val in beta-globin; HbS polymerizes when deoxygenated
4. 4Hereditary hemochromatosis — HFE C282Y iron overload; cirrhosis, diabetes, bronze skin in midlife
5. 5Marfan syndrome — fibrillin-1 defect; tall habitus, upward lens dislocation, aortic root dilation
6. 6Neurofibromatosis type 1 — café-au-lait macules, axillary freckling, Lisch nodules
7. 7Huntington disease — CAG repeat expansion; chorea plus psychiatric change, caudate atrophy
8. 8Anticipation — repeat expansion makes disease earlier and worse each generation
9. 9Duchenne muscular dystrophy — dystrophin frameshift; Gowers sign, calf pseudohypertrophy, high CK
10. 10Becker muscular dystrophy — in-frame dystrophin mutation, milder and later than its frameshift cousin
11. 11Hemophilia A — factor VIII deficiency; hemarthroses with prolonged PTT, normal PT
12. 12Familial adenomatous polyposis — APC mutation; hundreds of colonic polyps, near-certain cancer without colectomy
13. 13Lynch syndrome (HNPCC) — mismatch-repair mutation; early right-sided colon cancer plus endometrial cancer
14. 14BRCA1/BRCA2 — tumor-suppressor mutations behind hereditary breast and ovarian cancer
15. 15Trisomy 21 — single palmar crease, hypotonia, endocardial cushion defect, duodenal atresia
16. 16Trisomy 18 — clenched fists with overlapping fingers and rocker-bottom feet
17. 17Trisomy 13 — midline defects: cleft lip, holoprosencephaly, polydactyly
18. 18Turner syndrome — 45,X; short stature, streak ovaries, coarctation of the aorta
19. 19Klinefelter syndrome — 47,XXY; tall, small firm testes, gynecomastia, infertility
20. 20Nondisjunction — chromosomes fail to separate in meiosis; risk climbs with maternal age
21. 21Sweat chloride test — the diagnostic standard for cystic fibrosis; ≥60 mmol/L confirms
22. 22GINA — federal law barring health-insurance and employment discrimination on genetic results
23. 23Multifactorial inheritance — empiric recurrence risk that rises with each affected relative
24. 24Gowers sign — a child climbs up his own legs to stand from the floor

The distinctions that lose points on this material, year after year.

• Carrier probability for the unaffected sibling. An unaffected sibling of an autosomal recessive patient is a 2/3 carrier, not 1/2 — you must remove the affected genotype from the denominator, because the question told you the sibling is unaffected. This one probability trick shows up on nearly every genetics exam.
• X-linked recessive fathers. An affected father transmits the allele to ALL daughters (obligate carriers) and NO sons — sons get his Y. Students reflexively write 50% for everything; the 50% risks belong to a carrier mother's children.
• Dominant does not mean common or mild. BRCA and FAP are inherited dominantly even though the cellular mechanism is recessive loss of a tumor suppressor (the second hit is somatic). Marking 'tumor suppressor = recessive inheritance' is the classic conflation of cell-level and pedigree-level genetics.
• Duchenne vs Becker. Both are dystrophin, both X-linked recessive; the difference is frameshift/deletion with absent protein (Duchenne, severe, early) versus in-frame mutation with reduced protein (Becker, milder, later). Questions test the frame rule, not the gene.
• Turner is not trisomy and is not maternal-age-related. 45,X is a MONOSOMY, most often from loss of the paternal sex chromosome, and its incidence does not rise with maternal age the way trisomy 21 does. It is also the only aneuploidy compatible with life that has just 45 chromosomes.
• Anticipation direction. Anticipation means earlier onset and greater severity in LATER generations — students reverse it. In Huntington the largest expansions come through the father; in fragile X, through the mother.
• Hemophilia labs. Prolonged PTT with a NORMAL PT and normal platelets — intrinsic pathway factors VIII/IX. Choosing prolonged bleeding time or PT confuses hemophilia with von Willebrand disease or vitamin K problems.

Where this topic shows up again — in clinic, on rotations, and on the boards.

• Recurrent pulmonary infections + failure to thrive in an infant. Think cystic fibrosis: defective CFTR chloride transport dehydrates airway mucus (Pseudomonas and Staph colonization) and blocks pancreatic ducts (steatorrhea, fat-soluble vitamin deficiency). Confirm with sweat chloride ≥60 mmol/L; newborn screens flag elevated immunoreactive trypsinogen first. Nearly all affected males are infertile from congenital absence of the vas deferens.
• Painful vaso-occlusive crisis. Deoxygenated HbS polymerizes, sickled cells occlude microvasculature — bone pain, dactylitis in toddlers, acute chest syndrome, splenic autoinfarction by early childhood (hence encapsulated-organism risk and the need for pneumococcal vaccination and childhood penicillin prophylaxis). Hydroxyurea works by raising HbF, which interrupts polymerization.
• Tall patient with lens dislocation and a diastolic murmur. Marfan: fibrillin-1 is the scaffold for elastic fibers and normally sequesters TGF-β, so the aortic media degenerates — aortic root dilation, dissection risk, and aortic regurgitation. Echocardiographic surveillance and beta-blockade; counsel against high-intensity isometric sports. Upward lens dislocation distinguishes it from homocystinuria's downward dislocation.
• Middle-aged man with new diabetes, fatigue, and abnormal LFTs. Screen for hereditary hemochromatosis: transferrin saturation and ferritin first, HFE genotyping to confirm. Unchecked iron loading causes cirrhosis (with hepatocellular carcinoma risk), cardiomyopathy, hypogonadism, and arthropathy of the 2nd-3rd MCPs. Phlebotomy is the treatment; women present later because menses offload iron.
• Toddler who can't keep up and climbs up his legs to stand. Gowers sign plus calf pseudohypertrophy and a CK in the thousands points to Duchenne. Absent dystrophin destabilizes the muscle membrane; boys are wheelchair-dependent by adolescence, and death comes from cardiomyopathy and respiratory failure. Most mothers are carriers (though about a third of cases are new mutations) — the counseling conversation includes future pregnancies.
• Adult with chorea and a parent who 'died in a psychiatric hospital'. Huntington: dominant CAG expansion, full penetrance, no disease-modifying therapy. Predictive testing of asymptomatic relatives is done only with formal pre- and post-test counseling and the patient's own informed consent — never test an at-risk child at a parent's request.
• Primary amenorrhea in a short teenage girl. Turner until proven otherwise: streak ovaries mean low estrogen with HIGH FSH (hypergonadotropic hypogonadism). Screen for coarctation and bicuspid aortic valve, renal anomalies, and hypothyroidism; growth hormone and estrogen replacement are standard care.
• Dozens of colonic polyps on a screening colonoscopy at 25. FAP (APC): colorectal cancer is essentially certain without prophylactic colectomy, so first-degree relatives start sigmoidoscopy/colonoscopy in adolescence. Contrast Lynch syndrome: few polyps but rapid mismatch-repair-driven cancers — colonoscopy every 1-2 years starting in the 20s, plus endometrial cancer surveillance in women.