title: Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
abstract: 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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: Claudia
authors.initials: C
authors.lastname: Gonzaga-Jauregui
authors.forename: David
authors.initials: D
authors.lastname: Rio Deiros
authors.forename: David C Y
authors.initials: DC
authors.lastname: Chen
authors.forename: Lynne
authors.initials: L
authors.lastname: Nazareth
authors.forename: Matthew
authors.initials: M
authors.lastname: Bainbridge
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Chyn
authors.initials: C
authors.lastname: Jing
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: Amy L
authors.initials: AL
authors.lastname: McGuire
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Pawel
authors.initials: P
authors.lastname: Stankiewicz
authors.forename: John J
authors.initials: JJ
authors.lastname: Halperin
authors.forename: Chengyong
authors.initials: C
authors.lastname: Yang
authors.forename: Curtis
authors.initials: C
authors.lastname: Gehman
authors.forename: Danwei
authors.initials: D
authors.lastname: Guo
authors.forename: Rola K
authors.initials: RK
authors.lastname: Irikat
authors.forename: Warren
authors.initials: W
authors.lastname: Tom
authors.forename: Nick J
authors.initials: NJ
authors.lastname: Fantin
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D005808:Genes, Recessive; D056726:Genetic Association Studies; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense