Genetic Disorders & Single-Gene Diseases

🟢 Lite — Quick Review (1h–1d)

Rapid summary for last-minute revision before your exam.

Chromosomal disorders:

• Down syndrome (Trisomy 21): Mental retardation, flat facies, epicanthal folds, single palmar crease, sandal gap, congenital heart defects (AV canal defect most common), duodenal atresia, #1 cause of inherited intellectual disability
• Edwards syndrome (Trisomy 18): Micrognathia, rocker-bottom feet, clenched fists with overlapping fingers, congenital heart defects; most die before 1 year
• Patau syndrome (Trisomy 13): Holoprosencephaly, microcephaly, cleft lip/palate, polydactyly, congenital heart defects; most die before 1 year

Fragile X syndrome: CGG repeat expansion in FMR1 gene (Xq27.3); #1 inherited cause of intellectual disability; macro-orchidism, large ears, long face; anticipation

Huntington disease: CAG repeat (HTT gene, chromosome 4); chorea, dementia; autosomal dominant; anticipation; ** anticipation** (disease worsens and appears earlier in successive generations)

⚡ Exam tip: “Advanced paternal age” = new mutations; associated with achondroplasia (FGFR3), Marfan, neurofibromatosis. NOT Down syndrome (advanced maternal age is the risk factor).

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🟡 Standard — Regular Study (2d–2mo)

Standard content for students with a few days to months.

Chromosomal Disorders

Down Syndrome (Trisomy 21)

Incidence: 1 in 800 live births; risk increases with maternal age (1 in 400 at age 35; 1 in 100 at age 40)

Pathogenesis:

• Nondisjunction (95%): Meiotic error in maternal ovary (95%) or paternal; most common at meiosis I
• Robertsonian translocation (4%): Usually between chromosome 21 and 14; 50% of translocation cases are inherited from carrier parent
• Mosaicism (1%): Mitotic nondisjunction in early embryo → two cell lines (46/47); milder phenotype

Clinical features:

• Intellectual disability (mild to moderate)
• Craniofacial: Flat occiput, brachycephaly, flat facial profile, epicanthal folds, Brushfield spots (speckled iris), small ears, protruding tongue, single palmar crease (simian crease — 50% of patients), sandal gap (wide space between 1st and 2nd toes)
• Congenital heart defects (40–50%): Endocardial cushion defect (AV canal defect) — most common; VSD, PDA, ASD
• GI: Duodenal atresia (double bubble sign), Hirschsprung disease
• Hematologic: Acute lymphoblastic leukemia (ALL), acute megakaryoblastic leukemia; increased risk of leukemia
• Endocrine: Hypothyroidism, early-onset Alzheimer disease (chromosome 21 codes amyloid precursor protein)
• Other: Atlantoaxial instability (cervical spine), recurrent infections, short stature

Recurrence risk: Standard trisomy 21: 1% (increases with maternal age); Robertsonian translocation: If mother is carrier (der 21;21) → 100%, if father → 5–10%

Turner Syndrome (45,X)

• Karyotype: 45,X (most common); mosaic 45,X/46,XX; structural X abnormalities
• Clinical features: Short stature (most consistent), streak gonads (fibrous tissue, no follicles), primary amenorrhea, infertility, webbed neck (pterygium colli), shield chest, widely spaced nipples, lymphedema (hands and feet at birth — due to lymphatic dysplasia), coarctation of aorta (most common cardiac defect), horseshoe kidney, increased risk of aortic dissection
• Intelligence: Generally normal; may have nonverbal learning disabilities
• Neverbear children naturally; estrogen replacement required; pregnancies possible with donor oocytes

Klinefelter Syndrome (47,XXY)

• Karyotype: 47,XXY (most common); 46,XY/47,XXY mosaic; 48,XXXY
• Clinical features: Tall stature (eunuchoid — long limbs, sparse body hair), small, firm testes (most consistent finding), gynecomastia (due to estrogen/androgen imbalance), primary amenorrhea? No — this is in females (males have azoospermia), azoospermia → infertility, reduced testosterone → small penis; IQ slightly reduced
• Diagnosis: Prepubertal — often missed; diagnosis at puberty or infertility workup
• Labs: ↑FSH, ↑LH (loss of negative feedback), ↓testosterone, ↑estradiol
• Associated: Breast cancer (50-fold increased risk), varicosities, osteoporosis, autoimmune diseases

Fragile X Syndrome

• Inheritance: X-linked dominant with anticipation; most common inherited cause of intellectual disability; 2nd most common overall cause after Down syndrome
• Gene: FMR1 gene (Xq27.3); expansion of CGG trinucleotide repeat
  • Normal: 5–44 repeats
  • Premutation (carrier): 55–200 repeats (may expand to full mutation in offspring)
  • Full mutation: >200 repeats → methylation → gene silenced
• Pathogenesis: CGG expansion → hypermethylation of FMR1 promoter → transcriptional silencing → loss of FMRP (RNA-binding protein important for synaptic plasticity)
• Clinical: Intellectual disability (moderate-severe); long face, large ears, macroorchidism (enlarged testes — most characteristic post-pubertal feature), high-arched palate, hyperextensible joints, autism spectrum features, hyperactivity
• Anticipation: More repeats → earlier onset and more severe disease; especially paternal transmission of premutation → expansion occurs during maternal meiosis

Single Gene (Mendelian) Disorders

Autosomal Dominant

Marfan Syndrome

• Gene: FBN1 (fibrillin-1); chromosome 15q21
• Inheritance: AD; variable expressivity; 25% new mutations
• Pathogenesis: Fibrillin-1 is a structural component of microfibrils in extracellular matrix (found in blood vessels, zonular fibers of lens, bones); defect → weakened connective tissue
• Clinical (mnemonic: “long limbs, heart problems, lens problems”):
  • Skeletal: Tall stature, arachnodactyly (long fingers — Steinberg sign positive, wrist sign positive), pectus excavatum/carinatum, scoliosis, hypermobile joints, high-arched palate
  • Cardiovascular: Aortic root dilation → aortic regurgitation → aortic dissection (most common cause of death); mitral valve prolapse/regurgitation; cystic medial necrosis (degeneration)
  • Ocular: Ectopia lentis (superotemporal lens dislocation — lens dislocates UP and OUT); myopia, retinal detachment
  • Other: Dural ectasia, striae (skin), pneumothorax (tall thin habitus)
• Diagnosis: Ghent criteria (clinical + genetic); major criteria include aortic root dilation, ectopia lentis, dural ectasia
• Treatment: Beta-blockers (reduce aortic stress); surgical repair of aortic root; avoid competitive sports and contact sports

Ehlers-Danlos Syndrome (EDS)

• Multiple types; classical EDS (types I/II): COL5A1/COL5A2 gene mutations
• Features: Skin hyperelasticity (can be stretched excessively), hypermobile joints (joint dislocation, subluxations), fragile skin (bruising, poor wound healing, wide scars), mitral valve prolapse
• Vascular type (vEDS, type IV): COL3A1 mutation; fragile blood vessels (berry aneurysms, aortic dissection at young age), bowel perforation, uterine rupture; most severe type

Neurofibromatosis Type 1 (NF1)

• Gene: NF1 tumor suppressor gene; chromosome 17q11.2; codes neurofibromin (RAS GTPase-activating protein)
• Diagnostic criteria (≥2 of 7):
  1. ≥6 café-au-lait spots (>5mm prepubertal, >15mm postpubertal)
  2. ≥2 neurofibromas or 1 plexiform neurofibroma
  3. Axillary or inguinal freckling (Crowe’s sign)
  4. Optic glioma
  5. ≥2 Lisch nodules (iris hamartomas — harmless)
  6. Distinctive osseous lesion (sphenoid dysplasia, tibial pseudarthrosis)
  7. First-degree relative with NF1
• Complications: Optic nerve glioma, CNS tumors, malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, leukemia

Huntington Disease

• Gene: HTT gene; chromosome 4p16.3; CAG trinucleotide repeat (glutamine)
• Inheritance: AD; complete penetrance
• Pathogenesis: Gain of function (toxic polyglutamine protein); selective neuronal death in striatum (caudate and putamen) and cortex
• Clinical: Chorea (involuntary movements), psychiatric symptoms (depression, personality changes), dementia (subcortical type), ataxia, dystonia; typically presents age 35–45
• Anticipation: More CAG repeats → earlier onset and more severe disease; especially with paternal transmission (expansion during spermatogenesis)
• Diagnosis: Genetic testing; MRI shows caudate atrophy → “boxcar ventricles”

Autosomal Recessive

Cystic Fibrosis (CF)

• Gene: CFTR (Cystic Fibrosis Transmembrane Conductance Regulator); chromosome 7q31; most common lethal genetic disease in Caucasians
• Mutation: ΔF508 (deletion of phenylalanine at position 508) — most common; >2000 mutations described
• Pathophysiology: CFTR is a chloride channel; defect → thick, viscous secretions in lungs (recurrent Pseudomonas/H. influenzae infections, bronchiectasis), pancreas (exocrine insufficiency → malabsorption), sweat glands (↑Cl⁻ and Na⁺ in sweat → sweat chloride test diagnostic), reproductive tract (male infertility due to congenital bilateral absence of vas deferens — CBAVD; females: decreased fertility)
• Diagnosis: Sweat chloride test (>60 mEq/L diagnostic); nasal potential difference; newborn screening (immunoreactive trypsinogen — IRT)
• Treatment: Chest physiotherapy, Dornase alfa (recombinant DNase), inhaled tobramycin for Pseudomonas; pancreatic enzyme replacement; ivacaftor (CFTR potentiator) for G551D mutation

Phenylketonuria (PKU)

• Gene: PAH (phenylalanine hydroxylase); chromosome 12q24; AR
• Pathophysiology: Cannot convert phenylalanine → tyrosine → accumulation of phenylalanine → toxic to developing brain
• Clinical (if untreated): Intellectual disability (most severe if untreated in first 2 years), musty/mousy odor (phenylacetic acid in sweat and urine), fair skin/hair (↓melanin synthesis), eczema, seizures, cardiac defects
• Prevention: Newborn screening (Guthrie test — bacterial inhibition assay); low phenylalanine diet started in first 2 weeks of life prevents intellectual disability
• Maternal PKU: Uncontrolled maternal PKU → teratogenic (microcephaly, congenital heart defects, IUGR) even in genetically normal fetus

Lysosomal Storage Diseases

Disease	Enzyme Deficiency	Accumulated Substance	Key Features
Gaucher disease (Type 1)	Glucocerebrosidase	Glucocerebroside	Hepatosplenomegaly, bone crises, “crinkled paper” macrophages; ** Gaucher cells**
Niemann-Pick disease (Types A, B)	Sphingomyelinase	Sphingomyelin	Hepatosplenomegaly, neurodegeneration; foam cells (lipid-laden macrophages)
Tay-Sachs disease	Hexosaminidase A	GM2 ganglioside	Cherry-red spot on macula, neurodegeneration, seizures; common in Ashkenazi Jews
Pompe disease	α-glucosidase (acid maltase)	Glycogen (lysosomal)	Cardiomegaly (infantile); muscle weakness (adult); glycogen accumulation in lysosomes

Hemoglobinopathies

Sickle Cell Disease

• Gene: HBB (β-globin); chromosome 11p15; Glu6Val (E6V) substitution
• Inheritance: AR; heterozygous = sickle cell trait (HbAS — generally asymptomatic except in extreme hypoxia); homozygous = sickle cell disease (HbSS)
• Pathophysiology: Deoxygenated HbS polymerizes → RBCs sickle → vaso-occlusive crises; chronic hemolytic anemia
• Sickling triggers: Hypoxia, dehydration, acidosis, cold, infection
• Clinical: Vaso-occlusive crises (painful crises — dactylitis in children, acute chest syndrome, splenic sequestration crisis in children), chronic hemolytic anemia (jaundice, gallstones), priapism, leg ulcers, stroke, osteomyelitis (Salmonella > S. aureus)
• ** labs**: Sickle cells on peripheral smear; positive sickling test (sodium metabisulfite); Hb electrophoresis: HbSS (sickle cell disease), HbAS (trait), HbA absent in SS; ↑HbF in sickle cell disease
• Prevention: Newborn screening; penicillin prophylaxis (prophylactic penicillin V from 2 months until at least 5 years)
• Treatment: Hydroxyurea (↑HbF production), blood transfusions, stem cell transplant; L-glutamine, crizanlizumab (P-selectin inhibitor)

β-Thalassemia

• Gene: HBB; chromosome 11p15; AR
• Pathophysiology: Reduced or absent β-globin chain synthesis → α-chains precipitate → ineffective erythropoiesis + hemolysis
• β-Thalassemia major (Cooley anemia): Transfusion-dependent severe anemia; presents after 6 months (when HbF declines); hepatosplenomegaly, growth retardation, “chipmunk facies” (marrow expansion of facial bones), iron overload (cardiac, hepatic, endocrine); diagnosis: ↑HbA₂ (>3.5%), ↑HbF; treat with transfusions + iron chelation (deferoxamine, deferasirox)
• β-Thalassemia minor/trait: Mild anemia, microcytosis, target cells; usually asymptomatic; ↑HbA₂
• α-Thalassemia: Deletion of α-globin genes (2 on each chromosome 16 = 4 total); 4-gene deletion (—/—) = Hb Bart’s hydrops fetalis (no α-chains → γ4 = Hb Bart’s → severe fetal anemia → death); 3-gene deletion (—/αα-) = HbH disease (moderate hemolytic anemia)

Genomic Imprinting

• Prader-Willi syndrome: Loss of paternally expressed genes on chromosome 15q11–13 (maternal uniparental disomy 15 or paternal deletion); clinical: hyperphagia, obesity, hypogonadism, intellectual disability, small hands/feet, hypotonia
• Angelman syndrome: Loss of maternally expressed genes on chromosome 15q11–13 (paternal uniparental disomy 15 or maternal deletion); clinical: severe intellectual disability, ataxia, seizures, inappropriate laughter (“happy puppet”), microcephaly

Key NEET PG Pearls

1. Down syndrome: Most common chromosomal disorder; AV canal defect most common CHD; duodenal atresia; advanced maternal age risk factor
2. Turner syndrome: 45,X; short stature, webbed neck, streak gonads, coarctation of aorta; primary amenorrhea
3. Klinefelter: 47,XXY; tall eunuchoid male; small firm testes; azoospermia; gynecomastia
4. Fragile X: CGG repeat expansion (>200 = full mutation); #1 inherited cause of intellectual disability; macroorchidism
5. Marfan: FBN1; AD; tall, aortic root dilation, ectopia lentis; NO cognitive impairment
6. Huntington: CAG repeat; AD; chorea + dementia; anticipation (paternal transmission)
7. Cystic fibrosis: CFTR; AR; ΔF508 most common; recurrent pulmonary infections (Pseudomonas); pancreatic insufficiency; sweat chloride test
8. Sickle cell disease: Glu6Val in β-globin; vaso-occlusive crises; HbSS on electrophoresis; hydroxyurea
9. Prader-Willi vs Angelman: Both chromosome 15q11-13 but opposite parental origin
10. Advanced paternal age → new mutations (achondroplasia, Marfan, NF1); NOT Down syndrome

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