Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease

Am J Hum Genet. 2022 Jan 6;109(1):172-179. doi: 10.1016/j.ajhg.2021.12.002. Epub 2021 Dec 22.


It is well known that the length of the CAG trinucleotide expansion of the huntingtin gene is associated with many aspects of Huntington disease progression. These include age of clinical onset and rate of initial progression of disease severity. The relationship between CAG length and survival in Huntington disease is less studied. To address this, we obtained the complete Registry HD database from the European Huntington Disease Network and reanalyzed the time from reported age of disease onset until death. We conducted semiparametric proportional hazards modeling of 8,422 participants who had experienced onset of clinical Huntington disease, either retrospectively or prospectively. Of these, 826 had a recorded age of death. To avoid biased model estimates, retrospective onset ages were represented by left truncation at study entry. After controlling for onset age, which tends to be younger in those with longer CAG repeat lengths, we found that CAG length had a substantial and highly significant influence upon survival time after disease onset. For a fixed age of onset, longer CAG expansions were predictive of shorter survival. This is consistent with other known relationships between CAG length and disease severity. We also show that older onset age predicts shorter lifespan after controlling for CAG length and that the influence of CAG on survival length is substantially greater in women. We demonstrate that apparent contradictions between these and previous analyses of the same data are primarily due to the question of whether to control for clinical onset age in the analysis of time until death.

Keywords: Huntington Disease; disease natural history; epidemiology; survival analysis; trinucleotide expansion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Female
  • Genetic Predisposition to Disease*
  • Humans
  • Huntingtin Protein / genetics*
  • Huntington Disease / genetics*
  • Huntington Disease / mortality*
  • Male
  • Middle Aged
  • Mortality
  • Proportional Hazards Models
  • Trinucleotide Repeat Expansion*


  • Huntingtin Protein