Extending the Mutational Spectrum of SYNE1 Ataxia in Chinese Patients.

SYNE1 ataxia is recognized as a multisystemic neurodegenerative disorder globally. The complicated phenotypic spectrum, ranging from pure cerebellar ataxia to diverse combinations of non-cerebellar dysfunctions, poses significant challenges for clinical diagnosis and investigation of its underlying pathogenic mechanisms. Recent research has identified pathogenic variants in SYNE1 as a significant contributor to autosomal recessive ataxia in China. Our study aims to broaden the clinical and mutational spectrum of SYNE1 ataxia in China, and provide a better insight into the potential genotype-phenotype correlations. Clinical investigations were performed by two experienced neurologists. Peripheral venous blood was collected for genomic DNA extraction. Variants in SYNE1 were identified by whole-genome sequencing in a Chinese cohort of 45 unrelated index subjects with autosomal recessive ataxia. Interpretation of pathogenicity for variants was based on the American College of Medical Genetics and Genomics guidelines. The putative pathogenic variants were further confirmed by Sanger sequencing for segregation analysis. In this cohort, we identified three unrelated families presenting with SYNE1 ataxia (frequency: 6.7%; 3/45), and two novel truncating variants, including one compound heterozygous nonsense mutation (NM_033071.3: c.3901 C > T, p.Q1301*) and one homozygous splice mutation (NM_033071.3: c.16360-1G > A). Functional validation of the c.16360-1G > A variant revealed a 4-nt deletion of exon 86 in transcripts. Our findings expanded the genetic and phenotypic spectrum of SYNE1 ataxia and explored the potential genotype-phenotype correlation through a general literature review. This underscores the critical role of SYNE1 mutations in autosomal recessive ataxia within the Chinese population, highlighting their significant clinical implications.