Genetic Inheritance Patterns
Reading pedigrees and the concepts that break simple Mendelian rules
Mendelian modes and pedigree clues
Autosomal dominant (AD). One mutant allele is enough. Both sexes are affected, the trait appears in every generation (vertical transmission), and an affected heterozygote passes it to 50% of offspring; male-to-male transmission can occur. AD disorders often involve structural proteins or receptors and tend to present later (Huntington disease, Marfan syndrome, familial hypercholesterolemia).
Autosomal recessive (AR). Two mutant alleles are needed. AR disorders are often enzyme deficiencies with earlier, more severe onset. Affected individuals cluster among siblings (horizontal pattern), the trait often skips generations, and risk rises with consanguinity.
AR = enzymes and horizontal (siblings); AD = structural proteins and vertical.
X-linked recessive (XLR). Males are affected far more often because they are hemizygous. Fathers pass their Y, not their X, to sons, so there is no father-to-son transmission; affected males usually come through carrier mothers (an affected maternal uncle is a classic clue), and generations are often skipped. An affected father makes all daughters carriers and no sons affected.
X-linked dominant (XLD). Both sexes are affected. An affected father transmits to all daughters and no sons; an affected mother transmits to 50% of all children. Some XLD disorders are lethal in males.
Mitochondrial. Mitochondria come from the egg, so transmission is exclusively maternal, to children of both sexes; affected fathers never pass it on. Severity varies among maternally related relatives because of heteroplasmy — each cell carries a different mix of mutant and normal mtDNA. Muscle biopsy often shows ragged red fibers.
| Mode | Pedigree clue | Risk to offspring | Examples |
|---|---|---|---|
| AD | Vertical, both sexes, every generation | 50% if one parent affected | Huntington, Marfan, familial hypercholesterolemia |
| AR | Horizontal, skips generations, consanguinity | Carrier × carrier: 25% affected, 50% carriers | Enzyme deficiencies (e.g., PKU), cystic fibrosis, sickle cell |
| X-linked recessive | Mostly males, no father-to-son | Carrier mother: 50% of sons affected, 50% of daughters carriers | Hemophilia A/B, Duchenne, G6PD deficiency, Lesch-Nyhan, Fabry, Bruton agammaglobulinemia |
| X-linked dominant | Both sexes; affected father → all daughters | Affected mother: 50% of all children | Hypophosphatemic (vitamin D–resistant) rickets, Alport, fragile X, Rett |
| Mitochondrial | Maternal only, both sexes, variable severity | Affected mother may pass to all children | MELAS, MERRF, Leber hereditary optic neuropathy |
Recurrence risk and Hardy-Weinberg
Carrier crosses. Two unaffected carriers of an AR disease have, with each pregnancy, a 1/4 chance of an affected child, 1/2 of a carrier, and 1/4 of a noncarrier. An unaffected sibling of an affected child has a 2/3 chance of being a carrier, because the affected genotype is excluded.
Hardy-Weinberg. For a gene with two alleles, allele frequencies satisfy p + q = 1 and genotype frequencies satisfy p² + 2pq + q² = 1, where p² = homozygous unaffected, 2pq = heterozygous carriers, and q² = affected homozygotes. The equilibrium assumes no selection, mutation, or migration, random mating, and a large population. For an X-linked recessive disease, the frequency in males equals q and in females q².
Rare AR shortcut. When the disease is rare, p is nearly 1, so carrier frequency (2pq) ≈ 2q. Work it from prevalence: take the square root to get q, then double it.
Imprinting and X inactivation
Genomic imprinting. At certain loci only the maternal or only the paternal allele is expressed; the other is epigenetically silenced (by methylation). Disease results when the single active copy is deleted or mutated, or when uniparental disomy (both copies from one parent) leaves no active copy. The classic pair maps to chromosome 15q.
| Feature | Prader-Willi | Angelman |
|---|---|---|
| Missing activity | Paternal 15q genes | Maternal UBE3A |
| Mechanisms | Paternal deletion; maternal uniparental disomy | Maternal deletion or UBE3A mutation; paternal uniparental disomy |
| Features | Neonatal hypotonia and poor feeding, then hyperphagia and obesity; hypogonadism; intellectual disability | Ataxia, seizures, inappropriate laughter ("happy puppet"), severe intellectual disability |
Lyonization. Early in development each female cell randomly inactivates one X, which condenses into a Barr body; the choice is then inherited by that cell's descendants, making every female a mosaic. This explains why female carriers of X-linked disease show variable expression — some Duchenne carriers, for example, manifest muscle weakness.
Anticipation and trinucleotide repeats
Anticipation. Earlier onset and greater severity in each successive generation, caused by expansion of an unstable trinucleotide repeat as it passes through the germline. Huntington disease presenting at progressively younger ages is the textbook example.
| Disorder | Repeat | Inheritance | Hallmarks |
|---|---|---|---|
| Huntington disease | CAG | AD (chromosome 4) | Chorea, psychiatric change, dementia, caudate atrophy |
| Myotonic dystrophy | CTG | AD | Myotonia, cataracts, frontal balding, testicular atrophy, arrhythmia |
| Fragile X syndrome | CGG | X-linked (FMR1) | Intellectual disability, long face, large ears, macroorchidism |
| Friedreich ataxia | GAA | AR (frataxin) | Ataxia, hypertrophic cardiomyopathy, diabetes, kyphoscoliosis |
Terms that bend Mendelian rules
- Incomplete penetrance — not everyone with the genotype shows the phenotype at all (BRCA1).
- Variable expressivity — the same genotype produces different severity (the range of features in NF1).
- Pleiotropy — one gene produces several phenotypic effects (PKU affects skin, hair, and CNS).
- Locus heterogeneity — mutations at different loci produce the same phenotype (albinism).
- Allelic heterogeneity — different mutations in the same gene (the many β-thalassemia alleles).
Penetrance asks whether the phenotype shows at all; expressivity asks how much.
Loss of heterozygosity and the two-hit model. Tumor suppressor genes are recessive at the cellular level: cancer develops only after a second hit inactivates the remaining normal allele (Knudson two-hit hypothesis; RB1, NF1, VHL). In hereditary retinoblastoma the first hit is germline, so tumors are early and often bilateral; sporadic cases need two somatic hits and are usually unilateral. Oncogenes, by contrast, act dominantly — one activated allele suffices.