Rare loss-of-function variants in POLD1, PMS1 and FAN1 modify age at onset of motor symptoms in Huntington's disease
Gelfman, S.; Wang, R.; Campos, A. I.; Sul, J.-H.; Li, Q. S.; Alvarez, S.; Pounjara, V. K.; Wang, C.; Ali, T.; Zou, Y.; Marcketta, A.; Ghosh, A.; Watanabe, K.; Lachmann, A.; Adhikari, K.; Ziyatdinov, A.; Yu, S.; Averitt, A.; Paynter, A.; LeBlanc, M.; Jones, M.; Marchini, J.; Abecasis, G. R.; Lotta, L. A.; Baras, A.; Kwak, S.; Rosinski, J.; Vogt, T. F.; Ferreira, M. A. R.; Stahl, E. A.; Coppola, G.
Show abstract
Huntington's disease is a rare neurodegenerative disease 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, neuronal death and clinical disease progression. To identify genetic factors with a major impact on disease onset and progression, we genome sequenced 18,825 individuals for the ENROLL-HD study. Our results show rare inactivating mutations in three genes, all involved in DNA damage repair, are major determinants of age of onset for motor symptoms (n=10,610) and other clinical manifestations. Heterozygote carriers of predicted loss-of-function (pLoF) variants in POLD1 and PMS1 developed motor symptoms an average 20 years (n=3; P=1x10-5) and 7 years (n=6; P=2x10-3) later than non-carriers, respectively. Conversely, heterozygote carriers of pLoF variants in FAN1 (n=30) developed symptoms 10 years earlier (P=2x10-10). Our findings highlight therapeutic strategies and help predict age of onset for at-risk individuals.
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