Master Genetics
for USMLE Step 1
Access 30+ high-yield questions tailored for the 2026 syllabus. Includes AI-powered explanations and performance tracking.
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).
- Aneuploidy:
- 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
- Quickly interpret pedigrees for AD, AR, XD, XR. Remember no male-to-male transmission for X-linked disorders.
- Distinguish Genomic Imprinting (parental origin-specific expression) from simple deletion or Uniparental Disomy. Prader-Willi is paternal, Angelman is maternal.
- Associate common chromosomal disorders (Down, Turner, Klinefelter, DiGeorge) with their classic clinical features and genetic basis.
- Anticipation in a pedigree always points to trinucleotide repeat expansion disorders (e.g., Huntington, Fragile X).
- Understand and apply Hardy-Weinberg equilibrium assumptions and calculations for allele/genotype frequencies.
- Match diagnostic tests (Karyotyping, FISH, Array CGH, Sanger, NGS) to the appropriate size and type of genetic abnormality they detect.
Sample Practice Questions
A 45-year-old male presents to the clinic with progressive vision loss, cataracts, and muscle weakness. He reports difficulty relaxing his grip after shaking hands. His medical history includes type 2 diabetes mellitus and cardiac arrhythmias. He mentions that his mother also had cataracts and 'muscle problems.' His younger daughter, age 18, has recently been diagnosed with a severe form of the same condition, presenting with profound intellectual disability, severe muscle weakness, and cardiac involvement from early childhood. Which of the following genetic phenomena best explains the observed differences in disease severity and age of onset between the father and his daughter?
A 45-year-old man presents with a 2-year history of involuntary jerky movements, personality changes, and progressive cognitive decline. His father developed similar symptoms in his late 50s. Neurological examination reveals choreiform movements, dysarthria, and impaired executive function. Magnetic resonance imaging of the brain shows caudate atrophy. To confirm the diagnosis and assess the genetic basis of his condition, which molecular genetic technique would be most appropriate?
A newborn male presents with hypotonia, a flat facial profile, a single palmar crease, and upward slanting palpebral fissures. A chromosomal analysis is performed and reveals a karyotype of 47,XY,+21. The parents are both 28 years old and have no family history of chromosomal abnormalities. What is the most common cause of this patient's genetic condition?
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