What are the Mendelian inheritance patterns and how do you recognise them?
A Mendelian (single-gene) disorder follows from one gene, usually in one of four patterns that depend on where the gene lies and how many abnormal copies are needed. Mendel's three laws are dominance (one allele can mask another), segregation (each gamete carries one allele of a pair) and independent assortment (alleles of different genes assort separately, except when genes are linked on the same chromosome).
| Pattern | Copies needed | Who is affected | Classic pedigree clue |
|---|---|---|---|
| Autosomal dominant (AD) | One altered copy | Males and females equally | Vertical transmission — every generation; male-to-male transmission possible |
| Autosomal recessive (AR) | Two altered copies | Males and females equally | Horizontal — siblings, skips generations; parents unaffected carriers; consanguinity |
| X-linked recessive (XLR) | One copy in males (hemizygous); two in females | Mostly males | No male-to-male transmission; diagonal 'Knight's move' via carrier females |
| X-linked dominant (XLD) | One copy | Both sexes, females more often and usually milder | Affected father → all daughters, no sons; some forms lethal in males |
| Mitochondrial | mtDNA variant | Both sexes | Maternal inheritance — mothers pass it to all children; fathers never |
What are the features of autosomal dominant inheritance?
One altered allele is enough to cause disease. The mechanism may be haploinsufficiency (one normal copy makes too little product), a dominant-negative effect (the mutant protein interferes with the normal one) or gain of function. An affected heterozygote has a 50% risk of passing the variant to each child, whatever the sex.
- Vertical transmission — affected individuals appear in every generation and rarely skip one.
- New (de novo) mutations are common: the recurrence risk for unaffected parents is usually below 1%, whereas germline mosaicism in a parent can raise it as high as 50%.
- Both parents affected and heterozygous — each child has a 75% chance of being affected; a homozygous affected person transmits the trait to 100% of children and often has a more severe phenotype.
- Reduced penetrance and variable expressivity (section below) make the pedigree look irregular.
- Late-onset conditions can hide a dominant family history if carriers die before the usual age of onset.
| Disorder | Gene / key point |
|---|---|
| Huntington disease | HTT CAG repeat; shows anticipation |
| Marfan syndrome | FBN1 — defective fibrillin; strongly variable expressivity |
| Neurofibromatosis type 1 | NF1; about half of cases are new variants |
| Achondroplasia | FGFR3; about 80% are born to average-height parents (new variants) |
| Familial hypercholesterolaemia | LDLR, APOB or PCSK9 |
| Tuberous sclerosis complex | TSC1 / TSC2 — mTOR pathway; high proportion de novo |
What are the features of autosomal recessive inheritance?
Disease appears only when both alleles are non-functional; one normal allele (haplosufficiency) makes enough product. Affected people usually have unaffected carrier parents and unaffected children, so the disease skips generations and is seen in siblings — horizontal transmission.
- Carrier × carrier: 25% affected, 50% unaffected carriers, 25% unaffected non-carriers. Among unaffected children, 2/3 are carriers.
- Consanguinity markedly raises the chance of an AR disease in a family.
- Pseudodominance — an AR trait appears in successive generations when an affected (homozygous) person has a child with a carrier; each child then has a 50% chance of being affected, so the pedigree mimics AD.
| Disorder | Key point |
|---|---|
| Cystic fibrosis | CFTR — impaired epithelial ion transport |
| Sickle cell disease | Haemoglobinopathy; carriers have a mild phenotype that protects against malaria (incomplete dominance) |
| Beta-thalassaemia major | HBB variants |
| Phenylketonuria | Inborn error of amino-acid metabolism |
| Wilson disease | Copper accumulation |
| Hereditary haemochromatosis | Types 1, 2 and 3 are AR |
| Tay-Sachs disease | HEXA — progressive neurodegeneration |
How does X-linked inheritance work, and what is the Knight's move?
In females one X chromosome is randomly inactivated in each cell (Lyon hypothesis), which produces mosaicism and variable expression in carriers. A male has one X and is hemizygous: he passes his X to all daughters and his Y to all sons, so father-to-son transmission never occurs for X-linked traits.
| Feature | X-linked recessive | X-linked dominant |
|---|---|---|
| Typically affected | Males | Both sexes; females more often, usually milder |
| Affected father | All daughters carriers; no affected sons | All daughters affected; no sons affected |
| Carrier / affected mother | Carrier mother: 50% of sons affected, 50% of daughters carriers | Affected mother: 50% of every child affected |
| Pedigree pattern | Knight's move (affected grandfather → carrier daughter → affected grandson) | Often few or no affected males — many forms are lethal in male embryos |
| Pattern | Disorders |
|---|---|
| X-linked recessive | Haemophilia A and B, Duchenne and Becker muscular dystrophy, Lesch-Nyhan syndrome, Hunter syndrome (MPS II), Fabry disease, G6PD deficiency, X-linked agammaglobulinaemia, Wiskott-Aldrich syndrome, red-green colour blindness |
| X-linked dominant | Vitamin D-resistant (hypophosphataemic) rickets, incontinentia pigmenti (male-lethal), fragile X syndrome (classified X-linked dominant by NLM), most Alport syndrome (COL4A5) |
How are mitochondrial disorders inherited?
Mitochondrial DNA (mtDNA) is passed through the egg cell only, so variants in mtDNA are inherited from the mother. The disorder can appear in every generation, in males and females, but fathers do not pass it to sons or daughters. This is maternal inheritance.
- Leber hereditary optic neuropathy (LHON) — mtDNA point variants (complex I genes such as MT-ND4, MT-ND1, MT-ND6); presents in young males with sequential bilateral visual loss.
- MELAS — inherited in the mitochondrial (maternal) pattern.
- Kearns-Sayre syndrome — usually not inherited: it arises from a somatic mtDNA deletion after conception. A trap against the 'all mitochondrial disorders are maternal' rule.
- Not every 'mitochondrial disease' is mtDNA: many are AR or AD disorders of nuclear genes that make mitochondrial proteins.
What are penetrance and expressivity, and why do pedigrees skip?
| Term | Meaning | Example |
|---|---|---|
| Penetrance | Proportion of people with the variant who show any signs of the disorder. Less than 100% = reduced (incomplete) penetrance | BRCA1/2 variants: many but not all carriers develop cancer |
| Variable expressivity | Range or severity of features among people who all have the variant | Marfan syndrome — from tall, thin habitus only to life-threatening aortic disease; all share FBN1 variants |
Both phenomena mainly affect autosomal dominant disorders (occasionally AR) and are thought to reflect genetic, environmental and lifestyle modifiers. A carrier with reduced penetrance can look healthy yet still transmit the variant, which is how a dominant trait appears to 'skip' a generation.
What are anticipation and genomic imprinting?
Anticipation means signs appear earlier and more severely in successive generations. It is typical of trinucleotide repeat expansion disorders: Huntington disease (CAG; 40–50 repeats in adult-onset, over 60 in the juvenile form), myotonic dystrophy type 1 (DMPK) and fragile X syndrome (CGG repeat in FMR1).
Genomic imprinting means that a gene is active only on the copy from one parent; the parental origin is marked by methylation during egg or sperm formation. Imprinted genes cluster at 11p15 and 15q11–q13. Uniparental disomy (UPD) — both copies of a chromosome from one parent — can cause disease when an imprinted region is involved.
| Syndrome | Locus | Mechanisms | Key features |
|---|---|---|---|
| Prader-Willi | 15q11–q13 (paternal genes lost) | Paternal deletion (about 70%), maternal UPD (about 25%) | Behavioural problems, uncontrolled eating |
| Angelman | 15q11–q13, UBE3A (maternal copy active in neurons) | Maternal deletion (about 70%), UBE3A variant (10–20%), paternal UPD (small %) | Intellectual disability, impaired speech |
| Beckwith-Wiedemann | 11p15 | Abnormal imprinted genes on 11p | Accelerated growth, increased risk of tumours |
What traps do examiners set in inheritance questions?
- Pseudodominance in AR conditions with consanguinity — a 'vertical' pedigree that is really recessive.
- Germline mosaicism — unaffected parents of an AD child can still have a recurrence risk well above the population rate.
- Male-lethal X-linked dominant disorders: only females survive, so 'all affected are female' does not mean X-linked recessive.
- New mutation — over 99% of Rett syndrome cases and many achondroplasia, NF1 and TSC cases have no family history; a negative history does not exclude AD disease.
- Kearns-Sayre is mitochondrial yet usually sporadic.
- Fragile X is classified X-linked dominant by NLM although it behaves unusually (repeat expansion, anticipation).
- Polygenic / multifactorial diseases (heart disease, type 2 diabetes, schizophrenia) and chromosomal disorders do not follow Mendelian patterns — see chromosomal syndromes.