Exome sequencing allows for rapid gene identification in a Charcot‐Marie‐Tooth family

Abstract

Objective Charcot-Marie-Tooth (CMT) disease comprises a large number of genetically distinct forms of inherited peripheral neuropathies. The relative uniform phenotypes in many patients with CMT make it difficult to decide which of the over 35 known CMT genes are affected in a given patient. Genetic testing decision trees are therefore broadly based on a small number of major subtypes (eg, CMT1, CMT2) and the observed mutation frequency for CMT genes. Since conventional genetic testing is expensive many rare genes are not being tested for at all. Methods Whole-exome sequencing has recently been introduced as a novel and alternative approach. This method is capable of resequencing a nearly complete set of coding exons in an individual. We performed whole-exome sequencing in an undiagnosed family with CMT. Results Within over 24,000 variants detected in 2 exomes of a CMT family, we identified a nonsynonymous GJB1 (Cx32) mutation. This variant had been reported previously as pathogenic in X-linked CMT families. Sanger sequencing confirmed complete cosegregation in the family. Affected individuals had a marked early involvement of the upper distal extremities and displayed a mild reduction of nerve conduction velocities. Interpretation We have shown for the first time in a genetically highly heterogeneous dominant disease that exome sequencing is a valuable method for comprehensive medical diagnosis. Further improvements of exon capture design, next-generation sequencing accuracy, and a constant price decline will soon lead to the adoption of genomic approaches in gene testing of Mendelian disease.

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

“…31,[33][34][35] In our study, we showed that the coverage of a predefined list of genes associated with dHMN and overlapping disorders was sufficiently high to use exome sequencing as an initial diagnostic approach. In addition, the combined use of Sequenom MassARRAY to validate the genetic variants identified appeared to be a fast and powerful strategy.…”

“…[27][28][29] More recently, the use of exome sequencing for diagnostic purposes in genetic disorders with a high degree of genetic heterogeneity such as CMT is being explored. 30,31 Although the prize of exome sequencing is declining, the bioinformatic tools for analysis have improved and the coverage of the sequencing appears to be sufficiently high for use in the diagnostic setting, several technical and ethical challenges remain. 32 In particular, establishing the pathogenicity of newly identified genetic variants is often difficult and the possibility of finding unrelated finding requires further attention.…”

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study

“…[23][24][25][26] Participants were asked to rate their response to: 'for me, learning such a result would be' by rating 1-7 on six items anchored by 'a bad thing-not a bad thing' , 'not beneficial-beneficial' , 'harmful-not harmful' , 'not a good thing-a good thing' , 'not worthwhileworthwhile' , 'unimportant-important' . Ratings were averaged and Cronbach alpha scores ranged from 0.88 to 0.96 for the four result categories.…”

The inherited ataxias: Genetic heterogeneity, mutation databases, and future directions in research and clinical diagnostics

“…Exome sequencing in particular has demonstrated its utility in the identification of causal genes in a variety of Mendelian disorders including ataxia [Montenegro et al, 2011;Ng et al, 2010;Pierson et al, 2011]. Although exome sequencing is a useful tool in new gene discovery, issues of cost and significant data storage burden associated with processing exome samples prohibit the routine use of sequencing in a diagnostic setting.…”