Parent-of-origin differences of mutant HTT CAG repeat instability in Huntington's disease

Eur J Med Genet. 2011 Jul-Aug;54(4):e413-8. doi: 10.1016/j.ejmg.2011.04.002. Epub 2011 Apr 23.


Background: Huntington's disease (HD) is a progressive autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). The CAG domain of mutant HTT is unstable upon intergenerational transmission, however, little is known about the underlying mechanisms.

Methods: From the HD archives of the Leiden University Medical Centre DNA samples from all parent-offspring pairs involving 36 CAG repeats or more were selected. To minimize procedural variability, CAG repeat lengths in both mutant and normal HTT were reassessed using the same standardized protocol, which resulted in the identification of 337 parent-offspring transmissions. The effects of both parental (mutant and normal CAG repeat size, age and gender) and offspring (gender and season of conception) characteristics on CAG repeat instability were assessed.

Results: Paternal transmissions were often associated with CAG repeat expansion, whereas maternal transmissions mainly resulted in CAG repeat contraction (mean change: +1.76 vs. -0.07, p<0.001). Only in paternal transmissions larger mutant CAG repeat size was associated with a greater degree of CAG repeat expansion (β=0.73; p<0.001). Conversely, only in maternal transmissions larger CAG repeat size of the normal allele was associated with a greater degree of CAG repeat contraction (β=-0.07; p=0.029). Parental age, offspring gender and season of conception were not related to CAG repeat instability.

Conclusion: Our findings suggest a slight maternal contraction bias as opposed to a paternal expansion bias of the mutant HTT CAG repeat during intergenerational transmission, which only in the maternal line is associated with normal HTT CAG repeat size.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Female
  • Genomic Instability / genetics*
  • Humans
  • Huntingtin Protein
  • Huntington Disease / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Nerve Tissue Proteins / genetics*
  • Nuclear Proteins / genetics*
  • Penetrance
  • Sex Factors
  • Trinucleotide Repeat Expansion / genetics
  • Trinucleotide Repeats / genetics*
  • Young Adult


  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Nuclear Proteins