Molecular diagnosis of autosomal recessive cerebellar ataxia in the whole exome/genome sequencing era

Abstract

Autosomal recessive cerebellar ataxias (ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich’s ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore, an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of whole-exome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.

Keywords: Autosomal recessive cerebellar ataxia, Whole-exome sequencing, Whole-genome sequencing, Homozygosity mapping, Next generation sequencing

Core tip: Molecular diagnosis of autosomal recessive cerebellar ataxias (ARCA) is challenging due to clinical overlap and increased genetic heterogeneity. Although use of traditional techniques led to the identification of causative mutations in the past, the recent employment of novel technologies in this field, has initiated a new era in the molecular diagnosis of ARCA. Limitations such as small sized families, large numbers of candidate genes within mapped intervals and large sized genes hindered the timely discovery of ARCA genes using conventional Sanger sequencing. ARCA gene discovery and molecular diagnosis should be achievable at a much faster rate through the use of whole-genome or whole-exome sequencing technologies.