Genetics for Step 1: Inheritance, Repeats, Imprinting

bolt The 60-second version

check_circleAutosomal dominant: every generation, both sexes, 50% risk to children; often structural or receptor proteins (Marfan, ADPKD, familial hypercholesterolemia, NF1, Huntington).
check_circleAutosomal recessive: skips generations, both sexes, 25% risk when both parents are carriers; often enzyme deficiencies (CF, sickle cell disease, PKU).
check_circleX-linked recessive: mostly males, no male-to-male transmission, carrier mothers (DMD, hemophilia, G6PD deficiency).
check_circleHardy-Weinberg: p² + 2pq + q² = 1; for a rare recessive disease, carrier frequency ≈ 2q.
check_circleTrinucleotide repeats expand across generations (anticipation): Huntington (CAG), fragile X (CGG), myotonic dystrophy (CTG), Friedreich ataxia (GAA).
check_circleImprinting on 15q11–13: loss of the paternal copy causes Prader-Willi syndrome; loss of the maternal UBE3A causes Angelman syndrome.

target What you'll be able to do · aligned to USMLE Step 1 · Genetics

GENETICSIdentify inheritance patterns from pedigrees and examples.
GENETICSPerform Hardy-Weinberg and carrier-risk calculations.
GENETICSExplain trinucleotide repeats, anticipation, imprinting, and mitochondrial inheritance.
GENETICSRecognize the major autosomal and sex chromosome aneuploidies.

How genetics is tested on Step 1

Read the pedigree for who is affected, in which sex, and in which generations.

Inheritance patterns. Mitochondrial disease varies in severity because of heteroplasmy (a mix of normal and mutant mitochondria).

Term	Meaning	Example
Variable expressivity	Same genotype, different severity	Neurofibromatosis type 1
Incomplete penetrance	Not everyone with the genotype is affected	BRCA1 mutations
Pleiotropy	One gene affects many organ systems	PKU, Marfan syndrome
Locus heterogeneity	Different genes cause the same phenotype	Albinism
Loss of heterozygosity	The second allele of a tumor suppressor is lost	Retinoblastoma

Mosaicism (cells with different genotypes in one person) can make a disease milder or patchy.

Hardy-Weinberg calculations

Most questions start from disease frequency and ask for carriers.

Hardy-Weinberg. Assumes a large population, random mating, and no mutation, selection, or migration.

Repeats, imprinting, and mitochondria

Special mechanisms that break simple Mendelian rules.

Disorder	Mechanism	Key features
Huntington disease	CAG repeat (HTT), autosomal dominant; anticipation through the father	Chorea, depression, dementia; caudate atrophy
Fragile X syndrome	CGG repeat (FMR1), X-linked; hypermethylation	Most common inherited intellectual disability; long face, large jaw, macroorchidism, autism
Myotonic dystrophy	CTG repeat, autosomal dominant	Myotonia, cataracts, frontal balding, testicular atrophy, arrhythmias
Friedreich ataxia	GAA repeat (frataxin), autosomal recessive	Ataxia, hypertrophic cardiomyopathy, diabetes, kyphoscoliosis
Prader-Willi syndrome	Paternal 15q11–13 deleted (or maternal uniparental disomy)	Hyperphagia, obesity, hypotonia, hypogonadism, intellectual disability
Angelman syndrome	Maternal UBE3A deleted or mutated (or paternal uniparental disomy)	Seizures, ataxia, severe intellectual disability, inappropriate laughter
Mitochondrial (e.g., MELAS, LHON)	Maternal mtDNA; heteroplasmy	Myopathy with ragged red fibers, lactic acidosis, vision loss

Anticipation: the repeat expands in successive generations, so disease appears earlier or more severely.

Chromosomal syndromes

Most trisomies arise from maternal meiotic nondisjunction, which rises with maternal age.

Sex chromosome disorders. Both cause primary hypogonadism with high gonadotropins.

Down syndrome (trisomy 21): flat face, epicanthal folds, single palmar crease, atrioventricular septal defect, duodenal atresia, Hirschsprung disease, early Alzheimer disease, and increased leukemia risk.
Edwards syndrome (trisomy 18): clenched fists with overlapping fingers, rocker-bottom feet, micrognathia, heart defects; most die within a year.
Patau syndrome (trisomy 13): holoprosencephaly, cleft lip and palate, polydactyly, cutis aplasia.
Second-trimester quad screen in Down syndrome: ↓ AFP, ↓ estriol, ↑ β-hCG, ↑ inhibin A.

Worked example

Calculate carrier risk.

functions Worked example — cystic fibrosis risk

Cystic fibrosis affects about 1 in 2,500 newborns in a population. A man from this population, with no family history, has a sister with CF. Neither he nor his partner is affected. What is the chance their first child has CF?

q² = 1/2,500, so q = 1/50 and the partner's carrier risk ≈ 2q = 1/25.
His sister is affected, so both his parents are carriers. As an unaffected sibling, his chance of being a carrier is 2/3.
Risk that both are carriers = 2/3 × 1/25 = 2/75.
Each child of two carriers has a 1/4 chance: 2/75 × 1/4 = 1/150.

Answer. About 1 in 150.

Next in the roadmap

Inheritance & Genetic Disorders

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quiz Test yourself

Quick check — 3 questions

1. A disease affects 1 in 40,000 people (autosomal recessive). Carrier frequency is about:

2. Which disorder shows anticipation through paternal transmission?

3. A tall man with small firm testes, gynecomastia, and infertility most likely has:

Frequently asked questions

How can you tell X-linked recessive from autosomal dominant inheritance in a pedigree?expand_more

X-linked recessive disease affects mainly males and never passes from father to son; autosomal dominant disease affects both sexes and can pass father to son.

What is anticipation?expand_more

Earlier onset or greater severity in successive generations, caused by expansion of a trinucleotide repeat.

What causes Prader-Willi syndrome?expand_more

Loss of the paternally expressed genes on 15q11–13, by paternal deletion or maternal uniparental disomy.

Why are mitochondrial diseases inherited only from the mother?expand_more

Mitochondria in the zygote come from the egg, not the sperm.