Single Gene Disorders

Inheritance Patterns - Gene Game Rules

• Autosomal Dominant (AD): Vertical transmission. 50% offspring risk. Variable expressivity. New mutations.

• Autosomal Recessive (AR): Horizontal. Skips generations. 25% risk (carrier parents). Consanguinity ↑.

• X-linked Recessive (XLR): Males > Females. No male-to-male. Carrier ♀ → 50% sons affected.

• X-linked Dominant (XLD): Affected ♂ → all daughters. Affected ♀ → 50% offspring.

• Mitochondrial: Maternal. Affected ♀ → all offspring. Heteroplasmy.

• Key Concepts:

  • Penetrance: Genotype shows phenotype (%).
  • Expressivity: Severity varies.
  • Pleiotropy: 1 gene, multiple effects.
  • Anticipation: Worsens/earlier over generations.

• Pedigree: □ Male, ○ Female, Shaded=Affected.

⭐ For Autosomal Dominant, think vertical transmission (parent to child) and variable expressivity. Achondroplasia often arises from a new mutation (Advanced Paternal Age).

Autosomal Dominant - Top Dog Genes

• Marfan Syndrome
  • Gene: FBN1 (Fibrillin-1)
  • Features: Arachnodactyly, ectopia lentis, aortic root dilatation/dissection. 📌 FAME: Fibrillin, Arachnodactyly, Mitral valve prolapse, Ectopia lentis.
  • Clues: Ghent criteria, family history.
• Huntington Disease
  • Gene: HTT (Huntingtin); CAG repeats >39 for full penetrance.
  • Features: Chorea, cognitive decline, psychiatric disturbances.
  • Clues: Family history, genetic testing (CAG repeat count).
• Neurofibromatosis Type 1 (NF1)
  • Gene: NF1 (Neurofibromin)
  • Features: Café-au-lait macules (≥6), neurofibromas, Lisch nodules (iris hamartomas), optic glioma.
  • Clues: NIH diagnostic criteria.
• Achondroplasia
  • Gene: FGFR3 (Fibroblast Growth Factor Receptor 3)
  • Features: Rhizomelic short stature, macrocephaly, frontal bossing, trident hand.
  • Clues: Clinical features, characteristic X-ray findings.

⭐ Huntington Disease is characterized by anticipation, where the disease manifests earlier and more severely in successive generations due to expansion of CAG trinucleotide repeats.

Autosomal Recessive - Hidden Heirs

• Cystic Fibrosis (CF)
  • Gene: CFTR (ΔF508 common)
  • Defect: Defective chloride channel
  • Features: Recurrent lung infections, pancreatic insufficiency, meconium ileus, male infertility
  • Dx: Sweat chloride > 60 mEq/L, genetic tests, newborn screening
• Sickle Cell Anemia
  • Gene: HBB
  • Defect: HbS (abnormal β-globin)
  • Features: Vaso-occlusive crises, hemolytic anemia, dactylitis, acute chest syndrome
  • Dx: Hb electrophoresis, newborn screen
• Phenylketonuria (PKU)
  • Gene: PAH
  • Defect: ↓ Phenylalanine hydroxylase
  • Features: Intellectual disability, seizures, musty odor, eczema
  • Dx: Newborn screen (↑ Phenylalanine)
• Tay-Sachs Disease
  • Gene: HEXA
  • Defect: ↓ Hexosaminidase A
  • Features: Progressive neurodegeneration, cherry-red macula, exaggerated startle
  • Dx: Enzyme assay, genetic testing
• Thalassemias (α & β)
  • Gene: HBA1/2 (α), HBB (β)
  • Defect: ↓ Globin chain synthesis
  • Features: Microcytic anemia, hepatosplenomegaly, bone deformities (β-major)
  • Dx: Hb electrophoresis, CBC (↓MCV)

⭐ The most common mutation in Cystic Fibrosis is ΔF508 in the CFTR gene, leading to defective chloride transport and characteristically high sweat chloride levels.## Autosomal Recessive - Hidden Heirs

• Cystic Fibrosis (CF)
  • Gene: CFTR (ΔF508 common)
  • Defect: Defective chloride channel
  • Features: Recurrent lung infections, pancreatic insufficiency, meconium ileus, male infertility
  • Dx: Sweat chloride > 60 mEq/L, genetic tests, newborn screening
• Sickle Cell Anemia
  • Gene: HBB
  • Defect: HbS (abnormal β-globin)
  • Features: Vaso-occlusive crises, hemolytic anemia, dactylitis, acute chest syndrome
  • Dx: Hb electrophoresis, newborn screen
• Phenylketonuria (PKU)
  • Gene: PAH
  • Defect: ↓ Phenylalanine hydroxylase
  • Features: Intellectual disability, seizures, musty odor, eczema
  • Dx: Newborn screen (↑ Phenylalanine)
• Tay-Sachs Disease
  • Gene: HEXA
  • Defect: ↓ Hexosaminidase A
  • Features: Progressive neurodegeneration, cherry-red macula, exaggerated startle
  • Dx: Enzyme assay, genetic testing
• Thalassemias (α & β)
  • Gene: HBA1/2 (α), HBB (β)
  • Defect: ↓ Globin chain synthesis
  • Features: Microcytic anemia, hepatosplenomegaly, bone deformities (β-major)
  • Dx: Hb electrophoresis, CBC (↓MCV) (image)[08bd91ea-483f-48a3-94eb-ea85ca8684f6]

⭐ The most common mutation in Cystic Fibrosis is ΔF508 in the CFTR gene, leading to defective chloride transport and characteristically high sweat chloride levels.## Autosomal Recessive - Hidden Heirs

• Cystic Fibrosis (CF)
  • Gene: CFTR (ΔF508 common)
  • Defect: Defective chloride channel
  • Features: Recurrent lung infections, pancreatic insufficiency, meconium ileus, male infertility
  • Dx: Sweat chloride > 60 mEq/L, genetic tests, newborn screening
• Sickle Cell Anemia
  • Gene: HBB
  • Defect: HbS (abnormal β-globin)
  • Features: Vaso-occlusive crises, hemolytic anemia, dactylitis, acute chest syndrome
  • Dx: Hb electrophoresis, newborn screen
• Phenylketonuria (PKU)
  • Gene: PAH
  • Defect: ↓ Phenylalanine hydroxylase
  • Features: Intellectual disability, seizures, musty odor, eczema
  • Dx: Newborn screen (↑ Phenylalanine)
• Tay-Sachs Disease
  • Gene: HEXA
  • Defect: ↓ Hexosaminidase A
  • Features: Progressive neurodegeneration, cherry-red macula, exaggerated startle
  • Dx: Enzyme assay, genetic testing
• Thalassemias (α & β)
  • Gene: HBA1/2 (α), HBB (β)
  • Defect: ↓ Globin chain synthesis
  • Features: Microcytic anemia, hepatosplenomegaly, bone deformities (β-major)
  • Dx: Hb electrophoresis, CBC (↓MCV) (image)[08bd91ea-483f-48a3-94eb-ea85ca8684f6]

⭐ The most common mutation in Cystic Fibrosis is ΔF508 in the CFTR gene, leading to defective chloride transport and characteristically high sweat chloride levels.

X-Linked & Mitochondrial - Special Ops Genes

• X-Linked Recessive (XLR): No male-to-male transmission.

  • Duchenne/Becker Muscular Dystrophy (DMD/BMD): DMD gene. Muscle weakness, Gower's sign, calf pseudohypertrophy. Becker milder.
  • Hemophilia A/B: Factor VIII/IX deficiency. Bleeding, hemarthrosis, ↑aPTT.
  • G6PD Deficiency: G6PD gene. Hemolytic anemia (triggers: drugs, fava), Heinz bodies. 📌 Heinz = G6PD.

• X-Linked Dominant (XLD): Affected father → all daughters affected, no sons.

  • Fragile X Syndrome: FMR1 (CGG >200). ID, long face, macroorchidism. Anticipation.
  • Rett Syndrome: MECP2. Girls: neuro-regression, hand-wringing (lethal males).

• Mitochondrial: Maternal inheritance (mother to ALL offspring). Variable expressivity.

  • LHON: Bilateral vision loss.
  • MELAS: Mitochondrial Encephalopathy, Lactic Acidosis, Stroke-like episodes.

⭐ Affected XLR males transmit to all daughters (carriers), never sons. Gower's sign: classic in DMD.

High‑Yield Points - ⚡ Biggest Takeaways

• Autosomal Dominant: Vertical transmission, 50% offspring risk; Marfan syndrome, Huntington disease.
• Autosomal Recessive: Horizontal transmission (sibs), 25% offspring risk; consanguinity key; Cystic Fibrosis.
• X-linked Recessive: Affects males mainly, carrier females; no male-to-male transmission; Duchenne MD.
• X-linked Dominant: Affected fathers to all daughters, no sons; Rett syndrome.
• Mitochondrial Inheritance: Maternal transmission to all offspring; heteroplasmy (variable severity).
• Concepts: Penetrance, variable expressivity, pleiotropy, anticipation (Huntington's).
• Dynamic mutations: Expanding trinucleotide repeats cause Fragile X, Myotonic Dystrophy.