Abstract
Complex neurodegenerative conditions have occasionally been associated with copy-number gains. Using microarray and genome sequencing on DNA samples from eleven individuals from nine unrelated families, we show that copy-number gains at 16p13.3 cause a severe, recognizable disorder characterized by early-onset progressive ataxia and cognitive decline (9-32 years). Most affected individuals also displayed peripheral neuropathy and scoliosis. Optic atrophy, nystagmus, and dystonia were more variable features. The neuroradiological phenotype comprises a distinctive combination of atrophy of the cerebellum and caudate nuclei. Co-segregation data showed that the structural variant (SV) had occurred de novo in 5 individuals and, for one other individual, had been inherited from a mosaic, unaffected parent. Triplicated segments of 16p13.3 were identified within the duplications. Although these varied in size (30-811 kb), the minimal region of overlap included a single gene (ATP6V0C) that is highly expressed in the cerebellum. RNA sequencing (RNA-seq) using whole-blood and fibroblast/lymphoblast cultures indicated increased expression of several genes within the SV, with ATP6V0C showing the most significant increase (up to 4-fold). In most cases, the central segment of the SV was proven to be inverted and lay immediately distal to a 144 kb palindrome. Across 500,000 individuals from the UK Biobank, we identified 19 duplications but no triplications at this locus. Further analysis of the consequences of ATP6V0C overexpression on the stoichiometry within the vacuolar H+-ATPase heteromer and on neurological function will provide valuable pathomechanistic insights. Together, our findings define palindrome-mediated triplication on 16p13.3 as the cause of a clinically distinct childhood-onset neurodegenerative disorder.