Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

Abstract

Background: Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profiles of ARCA patients in the Chinese population.Methods: Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with Exome Depth. Likely causal CNV predictions were validated by CNVseq. Results: Thirty-eight mutations including 29 novel ones were identified in 25 out of 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, and the four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was firstly reported in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Furthermore, the clinical features of the patients carrying SACS, SYNE1and ADCK3 mutations were summarized. Conclusions: Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined CNV analysis in diagnosing suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data in making an accurate diagnosis.