F74 Origin-hd: genetic modifiers of htt cag intergenerational repeat instability in male hdgecs

Abstract

Background Earlier disease onset in subsequent generations, called anticipation, has been observed in HD families and is attributed to an increased CAG-repeat length in the HTT gene. CAG-repeat length mutations are referred to as ‘repeat instability’ and genome-wide association studies suggest that genomic variants function as genetic modifiers of disease onset, for example by affecting DNA repair mechanisms. Aims Origin-HD aims to investigate CAG repeat instability in germline and somatic cells and evaluate for correlations with putative genetic modifiers. Understanding the mechanisms affecting repeat instability may yield testable targets for future interventions. Study design Starting Q2 2019, over 1,000 male HDGECs (ages 18–55) will be recruited from Enroll-HD participants over about two years, approximately balanced between premanifest and manifest disease. Allele and genotype frequency for each pre-specified variant of interest will be assessed after about 500 participants have been recruited. If the predicted detectable effect size is d>0.35 in the final sample of 1,000 participants, a recruitment-by-genotype recruitment approach can be adopted in parallel to the ongoing recruitment. The repeat instability in DNA from sperm and blood of study participants will be analyzed, and genetic modifier variants will be determined.