CAG repeat expansions in exon 1 of the Huntingtin gene (HTT) cause Huntington’s disease (HD). Longer CAG repeat tracts correlate inversely with disease onset, but there remains considerable variation between individuals at the same repeat size (˜50%). A recent GWAS highlighted DNA repair genes as modifiers of HD onset. To improve our understanding of the effects of DNA repair genes we used whole-exome sequencing (WES) in an extreme onset cohort of HD to investigate rare coding modifiers of potentially large effect.Methods
Subjects were taken from the EHDN REGISTRY-HD study. An expected age at motor onset was calculated for each participant, and a motor onset residual was calculated by taking the CAG repeat length predicted age at onset from the observed motor onset. The 250 participants with the largest residuals at each extreme were selected for WES.Results
Typical HTT alleles have a penultimate CAA triplet in their structure (5’-CAGCAACAGCCG-3’). We find individuals possessing a pure CAG tract on their expanded HTT with no interruption have exclusively early HD onset. Conversely, additional CAA interruptions are associated with late onset disease (p=0.00014). These non-canonical alleles are uncommon (5.11% MAF across all allele types) but associated with large effects (10–20 years difference in onset).Conclusions
Non-canonical HTT alleles are likely cis-modifiers of disease onset. As CAG and CAA encode glutamine, these findings highlight the importance of the DNA repeat sequence itself in HD pathogenesis. We hypothesise that atypical CAG sequence modulates the propensity of the repeat to expand in neurons, affecting neurodegeneration and disease onset. We are currently exploring other next generation sequencing approaches to measure repeat instability of these atypical repeat alleles.