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

By J. R. Lupski, Jeffrey G. Reid, C. Gonzaga‐Jauregui, D. Deiros, David C. Chen, L. Nazareth, M. Bainbridge, H. Dinh, Chyn Jing, D. Wheeler and 12 more. New England Journal of Medicine, 2010

783 citations recorded by the source corpus.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Subfields: Cellular and Molecular Neuroscience, Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/e5e92582fb22cc8fefa5cc472ee85e5425e9d27b

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Citations in the corpus

Cleft lip and palate: synthesizing genetic and environmental influences (2011, positive): “Whole-exome sequencing has recently been successful in identifying causative genetic variants for Mendelian trait”
Association Mapping for Enhancing Maize (Zea mays L.) Genetic Improvement (2011, background): “However, there is currently no empirical validation of this target number of markers, and only resequencing via next generation sequencing may be able to provide this level of genotyping (Lupski et al., 2010) and only in species for which reference genomes are available.”
Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics (2011, background): “…advance, whole-exome and whole-genome sequencing will become feasible for large numbers of individuals; initial studies (Choi et al. 2009; Lupski et al. 2010; Ng et al. 2010) are promising, though they present a practical challenge of accurate identification of the lowest frequency…”
Sequencing technologies and genome sequencing (2011, methodology): “For the recent progress and development in domestic animals genome sequencing and assembling, a series of publications and studies were published(Table 3), for bovine ( Liu 2009; Elsik et al. 2009; Zimin et al. 2009), porcine (Wiedmann et al. 2008; Amaral et al. 2009; Ramos et al. 2009; Isom et al.”