We aim to elucidate landscape of degenerative ataxias in Japan through leveraging clinical information and comprehensive mutational analysis data.

Spinocerebellar degeneration (SCD) is a group of heterogeneous disorders composed of hereditary and sporadic ataxias: the majority of hereditary ataxias are autosomal-dominant SCD and the remaining are autosomal-recessive SCD or X-linked SCD in Japan. Clinical manifestations including natural history vary greatly among hereditary SCDs with different molecular backgrounds. We developed a cloud-based nation-wide registry system for SCDs, Japan Consortium of ATaxias (J-CAT). J-CAT has been designed to collect clinical information, conduct genetic diagnosis, provide framework to establish disease-specific natural history and establish resource repository.

On October 2019, 1227 patients were registered in J-CAT from all over Japan. DNA samples were obtained from 727 patients with informed consent in order to conduct comprehensive genetic analysis. All the DNA samples were subjected to the initial screening with PCR fragment analysis and repeat-primed PCR including SCA1, SCA2, MLD/SCA3 SCA6, SCA7, SCA8, SCA12, SCA17, SCA31, SCA36 and DRPLA. Whole exome sequencing (WES) was conducted for 159 patients whose initial mutational analysis was negative, prioritized for those with familial history or age at onset under 30.

Initial screening established the genetic diagnosis in 329 patients. The breakdown of the mutation-positive patients was as follows: 109 with SCA31, 97 with SCA6, 67 with MJD/SCA3, 23 with DRPLA, 14 with SCA2, 11 with SCA1, 6 with SCA8 and 1 with SCA36.  In addition, WES revealed mutations in genes causative for AD-SCD in 6 patients and for AR-SCD in 6 patients. In total, 341 patients (47%) were accounted for by known causative genes.

J-CAT has elucidated the landscape of degenerative ataxias in Japan, generating the most updated genetic epidemiological data. J-CAT contributes to enhancing diagnostic accuracy and providing the fundamental framework for clinical studies such as disease-specific natural history.