Rare loss-of-function variants in POLD1, PMS1 and FAN1 modify age at onset of motor symptoms in Huntington's disease

Loss-of-function variants in *POLD1*, *PMS1*, and *FAN1* (DNA repair) modify somatic CAG expansion and motor symptom onset age

A genomic study of 18,825 ENROLL-HD cohort individuals identified rare inactivating variants in three DNA repair genes as major determinants of motor symptom onset age in Huntington's disease. Heterozygous pLoF carriers in POLD1 and PMS1 develop symptoms an average of 20 and 7 years later than non-carriers. Conversely, FAN1 pLoF carriers (n=30) develop symptoms 10 years earlier (p=2×10⁻¹⁰). These findings confirm the central role of somatic CAG repeat expansion in clinical progression and designate these genes as potential therapeutic targets.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A modifier effect of ±10-20 years on onset age is considerable. The convergence on DNA repair genes opens a concrete therapeutic avenue: targeting somatic CAG triplet expansion. These data could improve genetic counseling for at-risk individuals carrying these modifier variants.