USMLE Step 1 Genetics High-Yield Facts

Genetics forms a foundational pillar of USMLE Step 1, integrating basic science with clinical reasoning. A firm grasp of inheritance patterns, risk calculations, and molecular mechanisms is essential for diagnosing disorders, counseling patients, and answering a significant number of exam questions efficiently. This review distills the highest-yield concepts you must know, moving from classic Mendelian inheritance to the nuanced exceptions that frequently appear on the test.

Core Inheritance Patterns and Associated Diseases

Mastering inheritance patterns allows you to predict disease risk in families and recognize classic presentations. Autosomal dominant disorders require only one mutated allele from an affected parent. They often involve structural proteins and exhibit variable expressivity (different severity among individuals) and incomplete penetrance (not all gene carriers show the disease). Key examples include Huntington disease, Neurofibromatosis type 1, Marfan syndrome, and Familial Hypercholesterolemia. A classic pedigree shows vertical transmission, affecting both sexes equally.

In contrast, autosomal recessive disorders require two mutated alleles, typically from asymptomatic carrier parents. These often involve enzyme deficiencies. Affected individuals are usually in a single sibilng generation (horizontal pedigree pattern). Consanguinity increases risk. Classic examples are Cystic fibrosis, Sickle cell disease, Tay-Sachs disease, and Phenylketonuria (PKU). Carriers (heterozygotes) are typically healthy but may have a selective advantage in certain environments (e.g., sickle cell trait and malaria resistance).

X-linked recessive disorders disproportionately affect males, who inherit the mutant allele from a carrier mother. There is no male-to-male transmission. Female carriers are usually asymptomatic but may show mild symptoms due to X-inactivation (lyonization). Think of Duchenne Muscular Dystrophy, Hemophilia A and B, Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Lesch-Nyhan syndrome. An affected male will pass the allele to all his daughters (making them carriers) but not to his sons.

X-linked dominant disorders are less common but crucial. They affect females more frequently than males (though often less severely), and there is no male-to-male transmission. A key feature is that an affected male will pass the condition to all his daughters and none of his sons. Examples include Hypophosphatemic rickets (Vitamin D-resistant rickets) and Alport syndrome (though some forms are autosomal).

Calculations, Pedigrees, and Chromosomal Abnormalities

The Hardy-Weinberg equation is a cornerstone for calculating carrier frequencies in population genetics. It states that for an autosomal recessive disease with allele frequencies $p$ (normal) and $q$ (disease), the genotypic frequencies are $p^2$ (homozygous normal), $2pq$ (carriers), and $q^2$ (affected). The critical assumptions are a large population, random mating, and no selection, mutation, or migration. For a disease like cystic fibrosis with an incidence ($q^2$) of 1 in 2500, $q=1/50=0.02$. The carrier frequency ($2pq$) is approximately $2(1)(0.02)=0.04$ or 1 in 25.

Analyzing pedigrees systematically is a key skill. Start by determining if the pattern is autosomal or sex-linked: if male-to-male transmission occurs, it cannot be X-linked. Then, assess if it is dominant (appears every generation) or recessive (skips generations). Remember, new mutations for dominant disorders are common.

Chromosomal abnormalities are frequently tested. Aneuploidy involves an abnormal number of chromosomes. Know these classics: Trisomy 21 (Down syndrome), Trisomy 18 (Edwards syndrome), Trisomy 13 (Patau syndrome), and sex chromosome aneuploidies like 47,XXY (Klinefelter syndrome) and 45,X (Turner syndrome). Chromosomal translocations include Robertsonian (fusion of two acrocentric chromosomes, e.g., 14;21 in familial Down syndrome) and reciprocal (exchange of material, which may be balanced or unbalanced).

Special Genetic Concepts: Anticipation, Imprinting, and Mitochondria

Step 1 loves testing the exceptions to standard Mendelian rules. Genetic anticipation describes the phenomenon where a genetic disorder becomes more severe or has an earlier onset in successive generations. This is caused by the expansion of trinucleotide repeat sequences. Prime examples are Huntington disease (CAG repeats, autosomal dominant), Fragile X syndrome (CGG repeats, X-linked dominant), and Myotonic dystrophy (CTG repeats, autosomal dominant).

Genomic imprinting involves the silencing of one parental allele based on its origin (maternal or paternal). The silenced allele is methylated. Diseases occur when the normally active allele is deleted or mutated. Prader-Willi syndrome results from the loss of paternal 15q11-13 (or maternal uniparental disomy), leading to hypotonia, obesity, and hypogonadism. Angelman syndrome results from the loss of maternal 15q11-13, causing seizures, ataxia, and inappropriate laughter.

Mitochondrial inheritance has unique features. Mitochondrial DNA is inherited exclusively from the mother (egg cytoplasm). It affects both males and females, but affected males cannot transmit the disease. Disorders often involve tissues with high energy demands: CNS, muscle, heart. Symptoms are highly variable due to heteroplasmy (a mix of normal and mutant mitochondria in each cell). Examples include Leber hereditary optic neuropathy (LHON) and MELAS (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes).

Cancer Genetics: Oncogenes vs. Tumor Suppressors

Distinguishing between oncogenes and tumor suppressor genes is a classic Step 1 question. Use the "gas pedal and brake" analogy. Oncogenes are mutated proto-oncogenes that promote cell growth; they act in a dominant "gain-of-function" manner. Only one mutated allele is needed to drive proliferation. Examples include RAS (pancreatic, colon CA), c-MYC (Burkitt lymphoma), and HER2/neu (breast CA).

Tumor suppressor genes normally inhibit cell cycle progression or promote apoptosis. They follow the "two-hit" hypothesis (Knudson hypothesis), requiring the loss of both alleles for loss of function. The first hit can be an inherited germline mutation, the second a somatic mutation. Examples include RB1 (retinoblastoma), TP53 (Li-Fraumeni syndrome), BRCA1/2 (breast/ovarian CA), and APC (colon CA). Remember, p53 is the "guardian of the genome" and is mutated in over 50% of all human cancers.

Common Pitfalls

1. Misapplying Hardy-Weinberg: The biggest error is using the equation for dominant disorders. It is strictly for calculating allele and carrier frequencies in autosomal recessive populations at equilibrium. Also, remember $p$ is approximately 1 for rare diseases.
2. Confusing X-linked Dominant with Autosomal Dominant: When you see a disease affecting multiple generations of both sexes, check for male-to-male transmission. If present, it rules out X-linked. If an affected father has no affected sons but all his daughters are affected, strongly consider X-linked dominant.
3. Mixing Up Genomic Imprinting Disorders: A simple mnemonic is "Prader-Willi = Paternal Want." The paternal allele is wanted/needed but is missing. For Angelman, think of the mother as an "Angel." The maternal allele is needed.
4. Overcomplicating Mitochondrial Pedigrees: Just look for maternal inheritance. All children of an affected female are at risk. Children of an affected male are not at risk. Don't look for classic Mendelian ratios.

Summary

• Inheritance Patterns: Autosomal dominant shows vertical transmission; autosomal recessive is horizontal, often with consanguinity. X-linked recessive affects males, with no male-to-male transmission. X-linked dominant affects all daughters of an affected male.
• Hardy-Weinberg: Use $p^2+2pq+q^2=1$ for autosomal recessive carrier frequency calculations. $q^2$ is disease incidence.
• Special Mechanisms: Genetic anticipation (earlier onset, more severe) is due to trinucleotide repeat expansion. Genomic imprinting is parent-of-origin specific silencing (Prader-Willi vs. Angelman). Mitochondrial inheritance is maternal only.
• Cancer Genetics: Oncogenes are "gas pedals" (dominant, gain-of-function). Tumor suppressors are "brakes" (recessive, two-hit loss-of-function).
• Chromosomal Abnormalities: Know the classic trisomies (21, 18, 13) and sex chromosome disorders (XXY, X). Robertsonian translocations involve acrocentric chromosomes.