Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy.
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.
Lupski
James R
JR
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Reid
Jeffrey G
JG
Gonzaga-Jauregui
Claudia
C
Rio Deiros
David
D
Chen
David C Y
DC
Nazareth
Lynne
L
Bainbridge
Matthew
M
Dinh
Huyen
H
Jing
Chyn
C
Wheeler
David A
DA
McGuire
Amy L
AL
Zhang
Feng
F
Stankiewicz
Pawel
P
Halperin
John J
JJ
Yang
Chengyong
C
Gehman
Curtis
C
Guo
Danwei
D
Irikat
Rola K
RK
Tom
Warren
W
Fantin
Nick J
NJ
Muzny
Donna M
DM
Gibbs
Richard A
RA
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
D018389:Codon, Nonsense