Abstract
BackgroundAlthough 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 profile of ARCA patients in the Chinese population.MethodsFifty-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 ExomeDepth. Likely causal CNV predictions were validated by CNVseq.ResultsThirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which 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 reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized.ConclusionsOur results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.
Highlights
Many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients
According to the American College of Medical Genetics and Genomics (ACMG) standard, 17 out of the 29 novel variants were classified as pathogenic variants, 10 as likely pathogenic variants, and the remaining two (ADCK3: p.R271H, SETX: p.Y2455C) as variants of uncertain significance, whose pathogenicity needed to be confirmed by further functional studies
One of the major highlights of the present study is the combination of whole-exome sequencing (WES) and copy number variation (CNV) analysis, and the results truly demonstrate that structural variation might not be extremely rare in ARCA
Summary
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 profile of ARCA patients in the Chinese population. Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare metabolic and degenerative genetic disorders that are characterized by progressive damage of the cerebellum and/or its associated afferent tracts [1, 2]. Despite the discovery of many disease-causing genes in recent years, the genetic cause of ARCAs remains elusive in more than 50% of affected individuals [2, 8, 9]. Due to the low incidence, few studies have reported the genetic or clinical characteristic of ARCA patients in the Chinese population
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