Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy

James R. Lupski, Jeffrey G. Reid, Claudia Gonzaga-Jauregui, David Rio Deiros, David C.Y. Chen, Lynne Nazareth, Matthew Bainbridge, Huyen Dinh, Chyn Jing, David A. Wheeler, Amy L. McGuire, Feng Zhang, Pawel Stankiewicz, John Halperin, Chengyong Yang, Curtis Gehman, Danwei Guo, Rola K. Irikat, Warren Tom, Nick J. Fantin & 2 others Donna M. Muzny, Richard A. Gibbs

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1181-1191
Number of pages11
JournalNew England Journal of Medicine
Volume362
Issue number13
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

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Charcot-Marie-Tooth Disease
Tooth
Genome
Mutation
Alleles
Genes
Phenotype
Inheritance Patterns
Inborn Genetic Diseases
Carpal Tunnel Syndrome
src Homology Domains
Human Genome
Haplotypes
Patient Care
DNA

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Deiros, D. R., Chen, D. C. Y., Nazareth, L., ... Gibbs, R. A. (2010). Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. New England Journal of Medicine, 362(13), 1181-1191. https://doi.org/10.1056/NEJMoa0908094
Lupski, James R. ; Reid, Jeffrey G. ; Gonzaga-Jauregui, Claudia ; Deiros, David Rio ; Chen, David C.Y. ; Nazareth, Lynne ; Bainbridge, Matthew ; Dinh, Huyen ; Jing, Chyn ; Wheeler, David A. ; McGuire, Amy L. ; Zhang, Feng ; Stankiewicz, Pawel ; Halperin, John ; Yang, Chengyong ; Gehman, Curtis ; Guo, Danwei ; Irikat, Rola K. ; Tom, Warren ; Fantin, Nick J. ; Muzny, Donna M. ; Gibbs, Richard A. / Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. In: New England Journal of Medicine. 2010 ; Vol. 362, No. 13. pp. 1181-1191.
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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.",
author = "Lupski, {James R.} and Reid, {Jeffrey G.} and Claudia Gonzaga-Jauregui and Deiros, {David Rio} and Chen, {David C.Y.} and Lynne Nazareth and Matthew Bainbridge and Huyen Dinh and Chyn Jing and Wheeler, {David A.} and McGuire, {Amy L.} and Feng Zhang and Pawel Stankiewicz and John Halperin and Chengyong Yang and Curtis Gehman and Danwei Guo and Irikat, {Rola K.} and Warren Tom and Fantin, {Nick J.} and Muzny, {Donna M.} and Gibbs, {Richard A.}",
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Lupski, JR, Reid, JG, Gonzaga-Jauregui, C, Deiros, DR, Chen, DCY, Nazareth, L, Bainbridge, M, Dinh, H, Jing, C, Wheeler, DA, McGuire, AL, Zhang, F, Stankiewicz, P, Halperin, J, Yang, C, Gehman, C, Guo, D, Irikat, RK, Tom, W, Fantin, NJ, Muzny, DM & Gibbs, RA 2010, 'Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy', New England Journal of Medicine, vol. 362, no. 13, pp. 1181-1191. https://doi.org/10.1056/NEJMoa0908094

Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. / Lupski, James R.; Reid, Jeffrey G.; Gonzaga-Jauregui, Claudia; Deiros, David Rio; Chen, David C.Y.; Nazareth, Lynne; Bainbridge, Matthew; Dinh, Huyen; Jing, Chyn; Wheeler, David A.; McGuire, Amy L.; Zhang, Feng; Stankiewicz, Pawel; Halperin, John; Yang, Chengyong; Gehman, Curtis; Guo, Danwei; Irikat, Rola K.; Tom, Warren; Fantin, Nick J.; Muzny, Donna M.; Gibbs, Richard A.

In: New England Journal of Medicine, Vol. 362, No. 13, 01.04.2010, p. 1181-1191.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy

AU - Lupski, James R.

AU - Reid, Jeffrey G.

AU - Gonzaga-Jauregui, Claudia

AU - Deiros, David Rio

AU - Chen, David C.Y.

AU - Nazareth, Lynne

AU - Bainbridge, Matthew

AU - Dinh, Huyen

AU - Jing, Chyn

AU - Wheeler, David A.

AU - McGuire, Amy L.

AU - Zhang, Feng

AU - Stankiewicz, Pawel

AU - Halperin, John

AU - Yang, Chengyong

AU - Gehman, Curtis

AU - Guo, Danwei

AU - Irikat, Rola K.

AU - Tom, Warren

AU - Fantin, Nick J.

AU - Muzny, Donna M.

AU - Gibbs, Richard A.

PY - 2010/4/1

Y1 - 2010/4/1

N2 - 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.

AB - 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.

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U2 - 10.1056/NEJMoa0908094

DO - 10.1056/NEJMoa0908094

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

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Lupski JR, Reid JG, Gonzaga-Jauregui C, Deiros DR, Chen DCY, Nazareth L et al. Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. New England Journal of Medicine. 2010 Apr 1;362(13):1181-1191. https://doi.org/10.1056/NEJMoa0908094