Core idea Inheritance describes how genetic information passes between generations and how genotype becomes phenotype. Mendelian ratios are models based on segregation and independent assortment; real patients often show incomplete penetrance, variable expressivity, mitochondrial transmission, imprinting, anticipation, polygenic effects or environmental modification.
Learning outcomes
Apply Mendel’s laws; construct Punnett squares and pedigrees; distinguish dominant, recessive, X-linked and mitochondrial patterns; explain incomplete dominance, codominance, allelic heterogeneity, epistasis, imprinting, anticipation, mosaicism and multifactorial inheritance; and communicate recurrence risk without treating a ratio as a diagnosis.
1. Mendel’s laws and the language of genetics
An allele is an alternative form of a gene at a locus. A homozygote has two identical alleles; a heterozygote has two different alleles. The genotype is the allele combination, while the phenotype is the observed trait produced through gene expression, development and environment. A dominant allele is expressed in a heterozygote; dominance does not mean common, stronger or more normal.
Segregation: the two alleles at a locus separate during meiosis so each gamete receives one. Independent assortment: alleles at different loci assort independently when loci are unlinked or far apart. Uniformity: crossing true-breeding parents can produce a uniform first-generation phenotype. Linkage, recombination and selection explain why real data may differ from simple ratios.
2. Mendelian inheritance patterns
| Pattern | Pedigree clues | Clinical examples |
|---|---|---|
| Autosomal dominant | Vertical transmission, both sexes, male-to-male transmission possible; affected heterozygote may have affected and unaffected children. | Marfan syndrome, Huntington disease, familial hypercholesterolaemia. |
| Autosomal recessive | Affected siblings with unaffected parents, both sexes equally, consanguinity may be present. | Sickle-cell disease, cystic fibrosis, phenylketonuria. |
| X-linked recessive | More affected males; no father-to-son transmission; carrier mothers may have affected sons. | Haemophilia, Duchenne muscular dystrophy. |
| X-linked dominant | Affected father transmits to all daughters and no sons; affected mother transmits to half of children. | Some forms of hypophosphataemic rickets. |
| Y-linked | Father-to-all-son transmission only. | Selected Y-chromosome infertility deletions. |
3. Probability and recurrence risk
For two heterozygous autosomal carriers, each pregnancy has a 25% chance of an affected child, 50% chance of a carrier child and 25% chance of an unaffected non-carrier child. These are independent probabilities for each pregnancy, not a quota. The chance of two affected children in succession is 1/4 × 1/4 = 1/16; the chance of at least one affected child in three pregnancies is 1 − (3/4)^3.
Use Bayes’ theorem when family history or a test changes the prior probability. The patient’s risk after testing depends on the sensitivity, specificity, likelihood ratio and starting risk. Never present a population risk as the individual’s risk without considering pedigree and phenotype.
4. Incomplete dominance and codominance
In incomplete dominance, the heterozygote has an intermediate phenotype; this does not mean the alleles blend permanently. In codominance, both alleles are expressed. The ABO blood-group system is a clinical example: IA and IB are codominant, while i is recessive. A person with IAIB expresses A and B antigens.
5. Multiple alleles, lethal alleles and allelic heterogeneity
A population may have many alleles at a locus even though each person carries only two. Lethal alleles can distort expected ratios because affected embryos may not survive to be counted. In allelic heterogeneity, different variants in the same gene produce the same disorder or different severities. In locus heterogeneity, variants in different genes produce a similar phenotype, making a single negative gene test insufficient.
6. Penetrance and variable expressivity
Penetrance is the proportion of people with a genotype who express a phenotype. Incomplete penetrance can make a dominant condition appear to skip generations. Expressivity is the range of manifestations among people with the same genotype. Explain these concepts when a family member carries a pathogenic variant but appears healthy or mildly affected.
7. Pleiotropy and epistasis
Pleiotropy occurs when one gene affects several organ systems; fibrillin-related Marfan syndrome can involve the skeleton, eyes and aorta. Epistasis occurs when one gene modifies or masks the effect of another. In humans, pathway interactions help explain why a variant does not create one isolated symptom but a network of findings.
8. Linkage and recombination
Genes close together on the same chromosome tend to travel together. Crossing-over during meiosis creates recombinant chromosomes, and recombination frequency estimates genetic distance in centimorgans. Linkage analysis can track a disease allele through a family when the causal variant is unknown, but recombination and phenocopies limit certainty.
9. Mitochondrial inheritance
Mitochondria are usually inherited through the oocyte, so an affected mother may transmit a mitochondrial variant to all children while an affected father generally does not transmit it. Heteroplasmy means a cell or person contains a mixture of normal and mutant mitochondrial genomes. The proportion and tissue distribution influence threshold effects, age of onset and severity.
10. Genomic imprinting and uniparental disomy
Imprinting marks genes according to parental origin, usually through DNA methylation and chromatin changes. A deletion or uniparental disomy may cause disease only when the altered chromosome comes from a particular parent. Prader–Willi and Angelman syndromes illustrate parent-of-origin effects involving chromosome 15, but molecular testing must determine the mechanism.
11. Anticipation and repeat expansion
In anticipation, a repeat expansion becomes larger or more unstable in successive generations, often causing earlier onset or greater severity. Huntington disease, myotonic dystrophy and fragile X-related disorders illustrate repeat dynamics, though the direction and parent-of-origin effect differ. A family history should record age at onset and exact molecular diagnosis rather than simply “runs in the family.”
12. Mosaicism and de novo variants
Mosaicism results from a post-zygotic mutation, so different tissues may carry different cell lines. A blood test can be negative when the relevant tissue is affected. A de novo variant appears newly in the patient and is absent from parental blood, but parental mosaicism can make recurrence risk higher than the usual low estimate.
13. Polygenic and multifactorial inheritance
Many common disorders result from several variants of small effect plus environment. Diabetes, hypertension, cleft lip and palate and neural-tube defects illustrate multifactorial patterns. Risk is often described as familial aggregation rather than a simple Mendelian percentage. Empiric recurrence data, family history, maternal health and environmental exposures guide counselling.
Do not force a Mendelian label: a pedigree can be distorted by small family size, reduced penetrance, adoption, misdiagnosis, non-paternity, early death, variable expression or incomplete records. Use molecular testing and specialist review when the pattern is unclear.
14. Applying inheritance in the clinic
Start with the phenotype and a three-generation pedigree. Confirm diagnoses and ages of onset. Identify the likely pattern, calculate the risk for each pregnancy, explain uncertainty and offer a test that can answer the clinical question. When a familial variant is known, targeted testing is usually more informative than an untargeted broad panel. Document who was tested, what specimen was used and what the result can exclude.
15. Examination summary
Mendel’s laws explain segregation and independent assortment, but clinical genetics adds penetrance, expressivity, linkage, mitochondrial inheritance, imprinting, repeat expansion, mosaicism, polygenic risk and environmental interaction. The correct recurrence-risk conversation links genotype, phenotype, pedigree, test performance and patient values; it never treats a ratio as a prediction of one guaranteed outcome.
