Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy

TLDR

Whole‑genome sequencing promises rapid disease‑gene identification, yet the abundance of rare, poorly characterized variants makes pinpointing pathogenic alleles in inherited disorders like Charcot‑Marie‑Tooth disease difficult. The study aimed to evaluate whether whole‑genome sequencing could provide a comprehensive diagnostic assay for a family with an unresolved recessive Charcot‑Marie‑Tooth disease. Researchers sequenced the proband’s genome, catalogued all functional variants in candidate genes, and genotyped these variants across family members, ultimately identifying compound heterozygous pathogenic alleles in SH3TC2. The two SH3TC2 mutations segregated independently with distinct subclinical phenotypes, and heterozygous carriers showed neuropathy susceptibility, demonstrating that whole‑genome sequencing can uncover clinically relevant variants and guide patient care.

Abstract

Whole-genome sequencing may revolutionize medical diagnostics through rapid identification of alleles that cause disease. However, even in cases with simple patterns of inheritance and unambiguous diagnoses, the relationship between disease phenotypes and their corresponding genetic changes can be complicated. Comprehensive diagnostic assays must therefore identify all possible DNA changes in each haplotype and determine which are responsible for the underlying disorder. The high number of rare, heterogeneous mutations present in all humans and the paucity of known functional variants in more than 90% of annotated genes make this challenge particularly difficult. Thus, the identification of the molecular basis of a genetic disease by means of whole-genome sequencing has remained elusive. We therefore aimed to assess the usefulness of human whole-genome sequencing for genetic diagnosis in a patient with Charcot-Marie-Tooth disease.We identified a family with a recessive form of Charcot-Marie-Tooth disease for which the genetic basis had not been identified. We sequenced the whole genome of the proband, identified all potential functional variants in genes likely to be related to the disease, and genotyped these variants in the affected family members.We identified and validated compound, heterozygous, causative alleles in SH3TC2 (the SH3 domain and tetratricopeptide repeats 2 gene), involving two mutations, in the proband and in family members affected by Charcot-Marie-Tooth disease. Separate subclinical phenotypes segregated independently with each of the two mutations; heterozygous mutations confer susceptibility to neuropathy, including the carpal tunnel syndrome.As shown in this study of a family with Charcot-Marie-Tooth disease, whole-genome sequencing can identify clinically relevant variants and provide diagnostic information to inform the care of patients.