Trinucleotide Repeat Expansion Disorders
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Direct answer
Trinucleotide repeat expansion disorders are inherited diseases in which a short run of three nucleotides multiplies beyond a threshold within a gene. Their hallmark is anticipation, meaning earlier onset and greater severity in successive generations, and the direction of this effect depends on where the repeat sits and which parent transmits it.
What you must remember
- Repeat threshold: normal alleles carry fewer repeats than the disease range, and in Huntington disease 40 or more CAG repeats give full penetrance.
- Anticipation: earlier onset and greater severity in successive generations, because repeats tend to expand during transmission.
- Huntington disease: a CAG repeat in HTT, autosomal dominant, with paternal transmission favouring expansion and juvenile onset.
- Fragile X syndrome: a CGG expansion in the 5' untranslated region of FMR1, X-linked, with methylation and silencing above 200 repeats.
- Myotonic dystrophy type 1: a CTG expansion in the 3' untranslated region of DMPK, where maternal transmission produces the congenital form.
- Friedreich ataxia: an autosomal recessive GAA expansion in intron 1 of FXN, reducing frataxin expression rather than altering the protein.
- Mechanism of toxicity: coding CAG repeats produce polyglutamine tracts, while noncoding repeats act through toxic RNA or transcriptional silencing.
How repeat location shapes the clinical pattern
The site of the repeat and the sex of the transmitting parent together determine the clinical pattern. Expansion is unstable during gametogenesis, so the same mutation can enlarge from one generation to the next, which is the basis of anticipation.
| Disorder | Repeat and site | Inheritance | Anticipation |
|---|---|---|---|
| Huntington disease | CAG in HTT exon 1 | Autosomal dominant | Paternal transmission; juvenile onset |
| Fragile X syndrome | CGG in FMR1 5' UTR | X-linked dominant | Maternal premutation expands |
| Myotonic dystrophy type 1 | CTG in DMPK 3' UTR | Autosomal dominant | Maternal transmission; congenital form |
| Friedreich ataxia | GAA in FXN intron 1 | Autosomal recessive | Not a prominent feature |
Expansion within the coding CAG tract causes protein toxicity, whereas intronic GAA repeats silence transcription, so the mechanism follows the repeat's location. Examiners usually ask about the parent of origin, so link paternal expansion to Huntington disease and maternal expansion to fragile X and congenital myotonic dystrophy. Repeat counts are read alongside the parent who transmitted the mutation.
Traps in repeat disorder questions
Most errors come from assuming that all repeat disorders behave like one another.
- Trap: assuming anticipation is equal for both parents Correct: paternal transmission favours expansion in Huntington disease, while maternal transmission drives expansion in fragile X and congenital myotonic dystrophy.
- Trap: calling Friedreich ataxia autosomal dominant because it has a repeat Correct: it is autosomal recessive, and the GAA repeat sits in an intron rather than the coding sequence.
- Trap: calling fragile X premutation carriers unaffected Correct: carriers may develop fragile X-associated tremor ataxia syndrome or premature ovarian insufficiency, so carrier status is not benign.
Frequently asked questions
Why does anticipation favour paternal transmission in Huntington disease?
Paternal transmission of the HTT CAG repeat tends to expand more than maternal transmission. This explains why the juvenile form, with earlier onset and greater severity, is usually inherited from the father.
What repeat count gives full penetrance in Huntington disease?
Forty or more CAG repeats in the HTT gene give full penetrance, so affected individuals almost always develop the disease. Repeat counts of 36 to 39 show reduced penetrance, while alleles of 26 or fewer are considered normal.
What is the difference between a premutation and a full mutation in fragile X syndrome?
A premutation carries roughly 55 to 200 CGG repeats and is usually unmethylated, so FMR1 remains expressed. A full mutation carries more than 200 repeats, leads to methylation and silencing of FMR1, and causes intellectual disability.
Why does congenital myotonic dystrophy occur in children of affected mothers?
Maternal transmission of the DMPK CTG expansion tends to enlarge the repeat markedly. The infant may therefore be born with severe hypotonia and respiratory failure, which is the congenital form of myotonic dystrophy type 1.