Whole exome sequencing in Japanese spinocerebellar ataxia identifies novel variants

Spinocerebellar degeneration (SCD) is a clinically and genetically diverse group, and the dominant form of SCD (AD-SCD) is generally referred to as spinocerebellar ataxia (SCA) that primarily affects the cerebellum. Some patients do not have a definitive genetic diagnosis but may carry unknown variants of known causative genes. Here, we screened for known SCA-associated genes in patients with suspected SCA. We examined 174 patients with SCA lacking abnormal repeat expansion of known causative genes. Whole-exome sequencing (WES) was performed to screen for variants in SCA-associated genes. The identified variants were confirmed by Sanger sequencing, and their pathogenicity was determined using five web-based algorithms. WES revealed novel single-nucleotide variants (SNVs) in three genes, ELOVL4, ELOVL5, and GRM1. Patients presented with symptoms other than cerebellar symptoms. One patient with an ELOVL4 variant exhibited skin changes, a typical symptom of ELOVL4 SCA, whereas the other ELOVL4 SCA patient had no skin changes and exhibited mild parkinsonism and calcification in the globus pallidus and dentate nucleus. The patient with an ELOVL5 variant exhibited bladder and rectal disturbances. Finally, patients with GRM1 variants showed few common features beyond the cerebellar symptoms. One patient showed white matter lesions, cognitive decline, and no-no head tremors, whereas the other showed spasticity. The identification of novel SNVs in these known SCA-associated genes will expand our understanding of the genetic landscape of SCA and facilitate the diagnosis of previously undiagnosed patients.