Genomic Landscape and Phenotypic Spectrum of Autosomal Recessive Cerebellar Ataxia in China

Autosomal recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous, often presenting as sporadic cases that pose a significant diagnostic challenge.

The aim was to characterize the clinical and mutational landscape of ARCA in the largest Chinese cohort using whole-genome sequencing (WGS).

We performed WGS on a cohort of 187 patients with suspected hereditary ataxia. Clinical severity was assessed using the Scale for the Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale. Pathogenicity was determined according to American College of Medical Genetics and Genomics guidelines, and variants were validated via Sanger sequencing and co-segregation analysis.

We identified 109 variants across 56 genes, with a rate of 79.8% (87/109) being novel. Definitive molecular diagnoses were achieved in 21 cases across 11 distinct subtypes. SYNE1 and SETX were the most frequent genetic contributors, with SETX truncating mutations (c.22_23insTA) associated with higher clinical burden. Multisystemic features were identified, including conjunctival telangiectasia in ATM, progressive action myoclonus in SCARB2, and spastic paraplegia in CAPN1.

In this study with, to date the largest Chinese cohort of ARCA, 87 novel variants were classified, which significantly expanded the genomic and phenotype landscape of ARCA in the Chinese population. © 2026 International Parkinson and Movement Disorder Society.