Repeat Expansion Disorders

Trinucleotide repeat disorders are caused by expansion of short tandem DNA repeats (most commonly 3-nucleotide units) beyond a pathogenic threshold. A hallmark feature is anticipation: the tendency for repeat length to increase across generations, leading to earlier onset and more severe disease in successive generations. The parent of origin often influences the likelihood and magnitude of expansion.

• Normal, premutation, and full mutation ranges: Each disorder has defined repeat thresholds. Normal alleles are stable; premutation alleles are prone to expansion but may not cause the classic phenotype; full mutation alleles cause disease.
• Anticipation: Clinical worsening across generations correlating with increasing repeat size. Not all trinucleotide repeat disorders show anticipation equally.
• Repeat location matters: Repeats in coding regions (e.g., CAG in Huntington disease) produce toxic polyglutamine tracts. Repeats in non-coding regions (e.g., CGG in FMR1 5'UTR, GAA in FXN intron) disrupt transcription or cause RNA toxicity.
• Parent-of-origin bias: Paternal transmission favors expansion in some disorders (Huntington disease, CAG), while maternal transmission favors expansion in others (Fragile X, CGG). This relates to differences in spermatogenesis vs oogenesis repeat instability.
• Somatic instability: Repeat length can vary across tissues in the same individual, contributing to variable phenotype and complicating molecular diagnosis.

• Fragile X syndrome (FMR1, CGG repeat): Normal <45, premutation 55-200, full mutation >200. Full mutation causes methylation and silencing of FMR1. Most common inherited cause of intellectual disability. Premutation carriers at risk for FXTAS (tremor/ataxia in older males) and FXPOI (premature ovarian insufficiency in females). Maternal transmission favors expansion to full mutation.
• Huntington disease (HTT, CAG repeat): Normal <27, intermediate 27-35, reduced penetrance 36-39, full penetrance >=40. Autosomal dominant neurodegenerative disorder with onset typically at 30-50 years. Juvenile HD (onset <20) associated with very large expansions (>60), usually paternally transmitted.
• Myotonic dystrophy type 1 (DMPK, CTG repeat): Normal 5-34, premutation 35-49, affected >=50. AD with multisystem features: myotonia, muscle weakness, cataracts, cardiac conduction defects, endocrine dysfunction. Congenital myotonic dystrophy (severe neonatal form) occurs with very large expansions (>1000), almost exclusively maternally transmitted.
• Friedreich ataxia (FXN, GAA repeat): Normal <33, premutation 34-65, affected 66-1700+. Autosomal recessive: the only common AR trinucleotide repeat disorder. GAA expansion in intron 1 causes reduced frataxin expression. Progressive ataxia, cardiomyopathy, and diabetes. ~96% of patients are homozygous for GAA expansion; ~4% are compound heterozygous with a point mutation.