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

Huntington's disease is a rare neurodegenerative disorder whose primary risk factors are inherited expansions of a CAG repeat tract in the HTT gene. Somatic expansion of these tracts leads to neuronal toxicity and death. The ENROLL-HD study genome sequenced 18,825 individuals to identify genetic factors impacting disease onset and progression. Rare inactivating mutations in three DNA damage repair genes (POLD1, PMS1, and FAN1) were found to be major determinants of age of onset for motor symptoms. Heterozygous carriers of predicted loss-of-function variants in POLD1 (n=3) and PMS1 (n=6) developed motor symptoms an average of 20 years and 7 years later than non-carriers, respectively. Conversely, carriers of FAN1 variants (n=30) developed symptoms 10 years earlier. These findings highlight therapeutic strategies and aid in predicting the age of onset for at-risk individuals.