Master Genetics
for USMLE Step 1

Core Concepts

Core genetics for USMLE Step 1 covers molecular processes, inheritance patterns, chromosomal disorders, and population genetics. Focus on high-yield examples and diagnostic principles.

• Molecular Basics:
  • DNA/RNA: Replication, Transcription, Translation. Key enzymes: DNA/RNA pol, helicase, ligase.
  • Mutations: Point (silent, missense, nonsense), Frameshift (indel not mult of 3), Splice site.
  • Trinucleotide Repeats: Expansion causes anticipation. Ex: Huntington (CAG), Myotonic Dystrophy (CTG), Fragile X (CGG), Friedreich Ataxia (GAA).
• Mendelian Inheritance:
  • Autosomal Dominant (AD): Vertical transmission, 50% risk, male-to-male. Ex: Huntington, Marfan, Neurofibromatosis 1.
  • Autosomal Recessive (AR): Horizontal, 25% risk (carrier parents), skipped generations, consanguinity. Ex: Cystic Fibrosis, Sickle Cell, PKU.
  • X-Linked Dominant (XD): No male-to-male. Fathers to all daughters. Ex: Fragile X (some presentations), Rett.
  • X-Linked Recessive (XR): No male-to-male. Sons of carrier mothers 50%. Males more affected. Ex: Hemophilia, Duchenne Muscular Dystrophy, G6PD deficiency.
  • Mitochondrial: Maternal inheritance (all children), heteroplasmy. Ex: Leber hereditary optic neuropathy (LHON), MELAS.
• Non-Mendelian Inheritance:
  • Genomic Imprinting: Gene expression based on parental origin (methylation). Ex: Prader-Willi (paternal deletion/maternal UPD), Angelman (maternal deletion/paternal UPD).
  • Mosaicism: Presence of genetically distinct cell lines within an individual.
  • Heterogeneity: Locus (different genes, same phenotype), Allelic (different mutations same gene, same phenotype).
• Chromosomal Abnormalities:
  • Aneuploidy:
    • Trisomy 21 (Down): ID, epicanthal folds, single palmar crease, cardiac defects.
    • Trisomy 18 (Edwards): Severe ID, micrognathia, clenched hands.
    • Trisomy 13 (Patau): Cleft lip/palate, polydactyly.
    • Turner (45, XO): Short stature, webbed neck, coarctation of aorta, primary amenorrhea.
    • Klinefelter (47, XXY): Tall stature, gynecomastia, small testes.
  • Structural: Deletions (DiGeorge 22q11 deletion), Translocations (Robertsonian).
• Hardy-Weinberg Principle: p^2 + 2pq + q^2 = 1 (genotype freq); p + q = 1 (allele freq). Assumes: no mutation, no migration, no selection, random mating, large population.

Clinical Presentation

• Highly variable, often multisystemic.
• Developmental delay, intellectual disability, dysmorphic features.
• Specific organ dysfunction (e.g., cardiac, renal, neurological).
• Metabolic crises (inborn errors of metabolism), cancer predisposition. Family history is key.

Diagnosis (Gold Standard)

• Karyotyping: For gross chromosomal abnormalities (aneuploidy, large translocations).
• FISH (Fluorescence In Situ Hybridization): For targeted microdeletions/duplications (e.g., DiGeorge, Prader-Willi).
• Array CGH (Comparative Genomic Hybridization): Genome-wide detection of copy number variants (deletions/duplications).
• PCR-based Methods: For trinucleotide repeats, specific point mutations.
• Sanger Sequencing: Gold standard for specific gene sequencing (point mutations, small indels).
• Next-Generation Sequencing (NGS) (Exome/Genome): High-throughput for panels, exomes, or whole genomes, especially for heterogeneous or unknown causes.
• Biochemical Assays: For inborn errors of metabolism (enzyme activity, metabolite levels).
• Prenatal: Amniocentesis, Chorionic Villus Sampling (CVS), Non-Invasive Prenatal Screening (NIPS).

Management (First Line)

• Supportive Care: Symptom management, rehabilitation, nutritional adjustments (e.g., PKU diet).
• Enzyme Replacement Therapy (ERT): For specific lysosomal storage diseases (e.g., Gaucher disease).
• Pharmacological Interventions: Targeted therapies for specific molecular defects (e.g., CFTR modulators for Cystic Fibrosis).
• Genetic Counseling: Essential for risk assessment, family planning, and education.
• Surveillance: Regular monitoring for associated complications (e.g., cancer screening).
• Gene Therapy: Emerging field for specific conditions (e.g., Spinal Muscular Atrophy).

Exam Red Flags