Length of Uninterrupted CAG, Independent of Polyglutamine Size, Results in Increased Somatic Instability, Hastening Onset of Huntington Disease

Galen E.B. Wright, Jennifer A. Collins, Chris Kay, Cassandra McDonald, Egor Dolzhenko, Qingwen Xia, Kristina Bečanović, Britt I. Drögemöller, Alicia Semaka, Charlotte M. Nguyen, Brett Trost, Fiona Richards, Emilia K. Bijlsma, Ferdinando Squitieri, Colin J.D. Ross, Stephen W. Scherer, Michael A. Eberle, Ryan K.C. Yuen, Michael R. Hayden

Research output: Contribution to journalArticlepeer-review


Huntington disease (HD) is caused by a CAG repeat expansion in the huntingtin (HTT) gene. Although the length of this repeat is inversely correlated with age of onset (AOO), it does not fully explain the variability in AOO. We assessed the sequence downstream of the CAG repeat in HTT [reference: (CAG)n-CAA-CAG], since variants within this region have been previously described, but no study of AOO has been performed. These analyses identified a variant that results in complete loss of interrupting (LOI) adenine nucleotides in this region [(CAG)n-CAG-CAG]. Analysis of multiple HD pedigrees showed that this LOI variant is associated with dramatically earlier AOO (average of 25 years) despite the same polyglutamine length as in individuals with the interrupting penultimate CAA codon. This LOI allele is particularly frequent in persons with reduced penetrance alleles who manifest with HD and increases the likelihood of presenting clinically with HD with a CAG of 36–39 repeats. Further, we show that the LOI variant is associated with increased somatic repeat instability, highlighting this as a significant driver of this effect. These findings indicate that the number of uninterrupted CAG repeats, which is lengthened by the LOI, is the most significant contributor to AOO of HD and is more significant than polyglutamine length, which is not altered in these individuals. In addition, we identified another variant in this region, where the CAA-CAG sequence is duplicated, which was associated with later AOO. Identification of these cis-acting modifiers have potentially important implications for genetic counselling in HD-affected families.

Original languageEnglish
Pages (from-to)1116-1126
Number of pages11
JournalAmerican Journal of Human Genetics
Issue number6
Publication statusPublished - Jun 6 2019


  • age of onset
  • CAG repeat
  • genetic modifier
  • Huntington disease
  • loss of interruption
  • polyglutamine
  • reduced penetrance alleles
  • somatic instability

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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