1. Introduction
Autosomal recessive cerebellar ataxias (ARCAs) are a complex group of disabling neurodegenerative disorders that manifest predominantly in childhood and early adulthood [1]. Despite increasing knowledge regarding the molecular basis of ARCA, a considerable number of patients remain without a specific diagnosis [2]. The diagnosis is challenging due to both genotypic and phenotypic heterogeneity [1]. More than 30 genes/loci have been associated with over 20 different clinical forms of ARCA [3]. Phenotypic variability in the expression of cerebellar impairment, including atypical phenotypes and overlapping clinical features, further complicates the picture [2]. The delineation of the precise clinical features ascribed to each ARCA remains under debate, hence complicating, yet also necessitating, a conclusive molecular diagnosis.
Mutations causative of different forms of ARCA are frequently located in genes of particularly large coding capacity (e.g., SYNE1 (NM_182961) 26 kb in 145 coding exons [4], SACS (NM_014363) 14 kb in 9 exons [5] and ATM (NM_000051) 9 kb in 62 coding exons [6]). Sanger-based (dideoxy) DNA sequencing is the gold standard for detecting mutations at the base pair level, but it is costly on an individual gene basis, and given the number and size of associated genes, its use in the investigation of unidentified ARCA is limited.
Here, we describe the application of high-density single nucleotide polymorphism (SNP) analysis and whole exome sequencing (WES) in the investigation of two Maori siblings presenting with apparent ARCA.