Novel mutations in typical and atypical genetic loci through exome sequencing in autosomal recessive cerebellar ataxia families

Abstract

Nearly a thousand mutations mapping to 60 different loci have been identified in cerebellar ataxias. However, almost 50% of the cases remain genetically uncharacterized and there is a difference in prevalence as well as in the phenotypic spectrum of ataxia among various geographical regions. This poses a challenge for setting up a genetic panel for screening ataxia. In our ataxic cohort of 1014 families, 61% are genetically uncharacterized (UC). We investigated the potential of whole exome sequencing in conjunction with homozygosity mapping (HM) to delineate the genetic defects in three uncharacterized families with recessive inheritance each manifesting some unusual phenotype: (i) infantile onset ataxia with hearing loss (IOAH), (ii) Juvenile onset cerebellar ataxia with seizures (JCS) and (iii) Friedreich ataxia-like (FA-like). We identified a novel missense mutation in c10orf2 in the family with IOAH, compound heterozygous mutations in CLN6 in the family with JCS and a homozygous frame-shift mutation in SACS in the FA-like patient. Phenotypes observed in our families were concordant with reported phenotypes of known mutations in the same genes thus obviating the need for functional validation. Our study revealed novel variations in three genes, c10orf2, CLN6, and SACS, that have so far not been reported in India. This study also demonstrates the utility of whole exome screening in clinics for early diagnosis.

Novel mutations in WWOX, RARS2, and C10orf2 genes in consanguineous Arab families with intellectual disability

“…2). C10orf2 mutations have been implicated in intellectual disability (Park et al 2014;Faruq et al 2014;Hartley et al 2012).…”

“…Twinkle is composed of three major functional domains: An N-terminal primase, a linker region required for proper helicase activity and oligomerization, and a C-terminal helicase (Shutt and Gray, 2006). C10orf2 mutations cause at least three distinct phenotypes: Perrault syndrome 5 (PRLTS5, OMIM 616138) (Morino et al 2014), Progressive external ophthalmoplegia with mitochordrial DNA deletions autosomal dominant 3 (PEOA3, OMIM 609286) (Spelbrink et al 2001;Echaniz-Laguna et al 2010), and Mitochondrial DNA depletion syndrome 7 (MTDPS7, OMIM 271245, also known as Infantile-onset Spinocerebellar Ataxia) (Nikali et al 2005;Hartley et al 2012;Park et al 2014;Faruq et al 2014); the latter phenotype is characterized by intellectual disability amongst others. It is thought that theinvolvement of multiple organ systems in those disorders is due to the mtDNA deletion and/or depletion caused by C10orf2 mutations.…”

Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia

“…A focused approach for NGS based investigations of autosomal recessive cerebellar ataxia (ARCA) cases are largely not reported except for a recent multicentric study that has shown a diagnostic yield of 31% by targeted gene analysis of patients of ataxia with onset below 25 years of age . Other than Friedreich's ataxia (FA), genetically confirmed other ARCA subtypes are rarely known in the Indian population except for few case studies including our previous report where we had observed novel variations in candidate ataxia genes, c10orf2 , SACS and CLN6 . In this study, we adopted an integrated “gene centric” approach combined with a family based study design to explore whole exomes and candidate gene exomes of ARCA cases.…”

“…are rarely known in the Indian population except for few case studies including our previous report where we had observed novel variations in candidate ataxia genes, c10orf2, SACS and CLN6. 7 In this study, we adopted an integrated "gene centric" approach combined with a family based study design to explore whole exomes and candidate gene exomes of ARCA cases. Table S1.…”

A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

“…We then performed whole exome sequencing of the affected child and her unaffected sibling (Figure B) using a Truseq exome (coding) enrichment kit (Illumina, Inc., San Diego, CA, USA) in accordance with the manufacturer's instructions. The analysis of whole exome sequencing data was performed using an approach essentially the same as that described previously . The WES data obtained after alignment were processed for variant calling using Unified Genotyper (GATK; http://www.broadinstitute.org/gatk).…”