General pathology · Genetic disease
Nonclassic inheritance: repeat expansions, mitochondrial genes, imprinting, mosaicism !
- Topic
Some genetic diseases break Mendel's rules: they worsen from one generation to the next, pass only through the mother, or depend on which parent gave the gene.
Updated 2026-11-01
What it is
Four mechanisms explain the exceptions to Mendelian inheritance: unstable triplet repeats that grow when passed on (anticipation), mitochondrial DNA genes inherited only from the mother, genomic imprinting that silences one allele according to its parent of origin, and mosaicism of the gonads or the body. Recognising them changes the family risk estimate completely.
Key facts
- Fragile X is the commonest inherited cause of intellectual disability and the second genetic cause after Down syndrome.
- Heteroplasmy: a cell holds both normal and mutant mitochondria; symptoms appear when the mutant ones exceed a threshold.
- Tissues with the highest energy demand (brain, muscle, heart, retina) are the most affected by mitochondrial diseases.
- Somatic mosaicism: the mutation arises after fertilisation and affects only part of the body, giving a partial picture.
Mechanisms of nonclassic inheritance
| Example | Mechanism | Key points | Inheritance |
|---|---|---|---|
| Fragile X syndrome | CGG repeat in the noncoding region of FMR1 | Intellectual disability, macro-orchidism after puberty, long face, autistic features; premutations cause ovarian insufficiency or adult tremor and ataxia | X-linked; expands in the mother |
| Huntington disease | CAG repeat in the coding region | Chorea, dementia and psychiatric change; caudate atrophy | Autosomal dominant; expands in the father |
| Myotonic dystrophy | Noncoding CTG repeat | Myotonia, cataracts, frontal balding, testicular atrophy, arrhythmias | Autosomal dominant |
| Friedreich ataxia | GAA repeat in an intron of frataxin | Ataxia, hypertrophic cardiomyopathy, diabetes | Autosomal recessive |
| MELAS | Mitochondrial DNA mutation | Encephalopathy, lactic acidosis, stroke-like episodes; ragged red fibres | Maternal |
| Prader-Willi and Angelman syndromes | Genomic imprinting at 15q11-q13 | The picture depends on whether the paternal or the maternal contribution is missing | By parent of origin |
Markers
- Ragged red fibres (Gomori trichrome)
- Raised lactate
- FMR1 Southern blot
- CAG repeat PCR
In the lab
- Repeat expansions are measured by PCR and Southern blot; the karyotype does not detect them reliably.
- In a muscle biopsy from a mitochondrial myopathy, Gomori trichrome shows ragged red fibres from the build-up of abnormal mitochondria.
- Raised lactate in blood or cerebrospinal fluid is typical of mitochondrial diseases.
Test yourself
Think of the answer, then tap the question to see it.
What is genetic anticipation?
Earlier and more severe onset of a disease in successive generations, because the triplet repeat lengthens as it is passed on.
Why does a father with a mitochondrial disease not pass it to his children?
Because the embryo's mitochondria come from the egg; those of the sperm are not kept.
Which testicular finding points to fragile X in an adolescent with intellectual disability?
Macro-orchidism, enlarged testes after puberty.
What explains two children of healthy parents having the same autosomal dominant disease?
Gonadal mosaicism: one parent carries the mutation in only part of their germ cells.
Related
- Mendelian inheritance: autosomal dominant, recessive and X-linked
- Genomic imprinting: Prader–Willi and Angelman
- How a single gene causes disease: enzymes, receptors and structural proteins
Related conditions
- Fragile X syndrome
- Huntington disease
- Myotonic dystrophy (types 1 and 2)
- Friedreich ataxia
- Spinocerebellar ataxias (autosomal dominant ataxias)
- MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes)
- Leigh syndrome
- Prader–Willi and Angelman syndromes (imprinting)
- Beckwith–Wiedemann syndrome
- Autism spectrum disorder (ASD)
- Primary ovarian insufficiency
Elsewhere in DurgiPedia
- Trinucleotide repeat expansion disorders
- Epigenetics: DNA and histone methylation
- Electron transport chain and oxidative phosphorylation
- Types of mutations
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Fragile X syndrome: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); What are the different ways a genetic condition can be inherited?: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026).
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Representative model, for educational purposes only.