The Experts below are selected from a list of 73959 Experts worldwide ranked by ideXlab platform
Josephine M Bryant - One of the best experts on this subject based on the ideXlab platform.
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Personalizing therapy for multidrug resistant TB: the potential of Rapid Whole Genome Sequencing
Expert Review of Anti-infective Therapy, 2015Co-Authors: Josephine M Bryant, Marc Lipman, Judith BreuerAbstract:Multidrug resistant tuberculosis is an increasing problem globally. The current gold standard in drug sensitivity testing is slow and cumbersome. To tackle drug resistance effectively, a more rapid method of testing is required. Current molecular tests are fast, but only offer information on a limited number of genetic loci. Whole Genome Sequencing presents an attractive alternative that can provide comprehensive, clinically relevant information on all described loci. Although the standard approach to Whole Genome Sequencing of Mycobacterium tuberculosis is slow due to the requirement of culture, this article will describe recent advances that mean it has the potential to provide results within days.
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Whole Genome Sequencing to establish relapse or re infection with mycobacterium tuberculosis a retrospective observational study
The Lancet Respiratory Medicine, 2013Co-Authors: Josephine M Bryant, Julian Parkhill, Simon R Harris, Rodney Dawson, Andreas H Diacon, Paul D Van Helden, Aziah A Mahayiddin, Charoen Chuchottaworn, Ian Sanne, Cheryl LouwAbstract:Summary Background Recurrence of tuberculosis after treatment makes management difficult and is a key factor for determining treatment efficacy. Two processes can cause recurrence: relapse of the primary infection or re-infection with an exogenous strain. Although re-infection can and does occur, its importance to tuberculosis epidemiology and its biological basis is still debated. We used Whole-Genome Sequencing—which is more accurate than conventional typing used to date—to assess the frequency of recurrence and to gain insight into the biological basis of re-infection. Methods We assessed patients from the REMoxTB trial—a randomised controlled trial of tuberculosis treatment that enrolled previously untreated participants with Mycobacterium tuberculosis infection from Malaysia, South Africa, and Thailand. We did Whole-Genome Sequencing and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing of pairs of isolates taken by sputum sampling: one from before treatment and another from either the end of failed treatment at 17 weeks or later or from a recurrent infection. We compared the number and location of SNPs between isolates collected at baseline and recurrence. Findings We assessed 47 pairs of isolates. Whole-Genome Sequencing identified 33 cases with little genetic distance (0–6 SNPs) between strains, deemed relapses, and three cases for which the genetic distance ranged from 1306 to 1419 SNPs, deemed re-infections. Six cases of relapse and six cases of mixed infection were classified differently by Whole-Genome Sequencing and MIRU-VNTR. We detected five single positive isolates (positive culture followed by at least two negative cultures) without clinical evidence of disease. Interpretation Whole-Genome Sequencing enables the differentiation of relapse and re-infection cases with greater resolution than do genotyping methods used at present, such as MIRU-VNTR, and provides insights into the biology of recurrence. The additional clarity provided by Whole-Genome Sequencing might have a role in defining endpoints for clinical trials. Funding Wellcome Trust, European Union, Medical Research Council, Global Alliance for TB Drug Development, European and Developing Country Clinical Trials Partnership.
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Whole Genome Sequencing for rapid susceptibility testing of m tuberculosis
The New England Journal of Medicine, 2013Co-Authors: Claudio U Koser, Josephine M Bryant, Jennifer Becq, Estee M Torok, Matthew J Ellington, Marc A Martirenom, A J Carmichael, Julian Parkhill, Geoffrey Paul Smith, Sharon J PeacockAbstract:As reported here, Whole-Genome Sequencing has the potential to rapidly facilitate the determination of antimicrobial susceptibility, especially for slower-growing pathogens, such as Mycobacterium tuberculosis.
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inferring patient to patient transmission of mycobacterium tuberculosis from Whole Genome Sequencing data
BMC Infectious Diseases, 2013Co-Authors: Josephine M Bryant, Simon R Harris, Anita C Schurch, Henk Van Deutekom, Jessica L De Beer, Victor De Jager, Kristin Kremer, Sacha A F T Van HijumAbstract:Background: Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of Whole Genome Sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the Genome over relevant timescales is required. Methods: We attempted to estimate a molecular clock by Sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years. Results: Multiple analyses support an average mutation rate of ~0.3 SNPs per Genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links. Conclusions: This in-depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of Whole Genome Sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the Whole Genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine Whole Genome Sequencing.
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Rapid Whole-Genome Sequencing for Investigation of a Suspected Tuberculosis Outbreak
Journal of Clinical Microbiology, 2012Co-Authors: M. E. Torok, Claudio U Koser, Josephine M Bryant, Matthew J Ellington, Geoffrey Paul Smith, Sandra Reuter, S. V. Stinchcombe, B. Nazareth, Stephen D. Bentley, Julian ParkhillAbstract:Two Southeast Asian students attending the same school in the United Kingdom presented with pulmonary tuberculosis. An epidemiological investigation failed to link the two cases, and drug resistance profiles of the Mycobacterium tuberculosis isolates were discrepant. Whole-Genome Sequencing of the isolates found them to be genetically identical, suggesting a missed transmission event.
Amy L Mcguire - One of the best experts on this subject based on the ideXlab platform.
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Whole Genome Sequencing in a patient with charcot marie tooth neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, Claudia Gonzagajauregui, J G Reid, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Amy L McguireAbstract: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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Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Jeffrey S. Reid, Claudia Gonzaga-jauregui, Amy L McguireAbstract: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.
Matthew N Bainbridge - One of the best experts on this subject based on the ideXlab platform.
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Whole Genome Sequencing for optimized patient management
Science Translational Medicine, 2011Co-Authors: Matthew N Bainbridge, Wojciech Wiszniewski, David R Murdock, Jennifer Friedman, Claudia Gonzagajauregui, Irene Newsham, J G Reid, John K Fink, Margaret MorganAbstract:Whole-Genome Sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete Genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)–responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-Genome Sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.
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Whole Genome Sequencing in a patient with charcot marie tooth neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, Claudia Gonzagajauregui, J G Reid, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Amy L McguireAbstract: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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Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Jeffrey S. Reid, Claudia Gonzaga-jauregui, Amy L McguireAbstract: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.
Simon R Harris - One of the best experts on this subject based on the ideXlab platform.
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Read and assembly metrics inconsequential for clinical utility of Whole-Genome Sequencing in mapping outbreaks
Nature Biotechnology, 2020Co-Authors: Simon R Harris, Sharon J Peacock, M. E. Torok, Edward J. P. Cartwright, Michael A. Quail, Julian ParkhillAbstract:Read and assembly metrics inconsequential for clinical utility of Whole-Genome Sequencing in mapping outbreaks
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Whole Genome Sequencing to establish relapse or re infection with mycobacterium tuberculosis a retrospective observational study
The Lancet Respiratory Medicine, 2013Co-Authors: Josephine M Bryant, Julian Parkhill, Simon R Harris, Rodney Dawson, Andreas H Diacon, Paul D Van Helden, Aziah A Mahayiddin, Charoen Chuchottaworn, Ian Sanne, Cheryl LouwAbstract:Summary Background Recurrence of tuberculosis after treatment makes management difficult and is a key factor for determining treatment efficacy. Two processes can cause recurrence: relapse of the primary infection or re-infection with an exogenous strain. Although re-infection can and does occur, its importance to tuberculosis epidemiology and its biological basis is still debated. We used Whole-Genome Sequencing—which is more accurate than conventional typing used to date—to assess the frequency of recurrence and to gain insight into the biological basis of re-infection. Methods We assessed patients from the REMoxTB trial—a randomised controlled trial of tuberculosis treatment that enrolled previously untreated participants with Mycobacterium tuberculosis infection from Malaysia, South Africa, and Thailand. We did Whole-Genome Sequencing and mycobacterial interspersed repetitive unit-variable number of tandem repeat (MIRU-VNTR) typing of pairs of isolates taken by sputum sampling: one from before treatment and another from either the end of failed treatment at 17 weeks or later or from a recurrent infection. We compared the number and location of SNPs between isolates collected at baseline and recurrence. Findings We assessed 47 pairs of isolates. Whole-Genome Sequencing identified 33 cases with little genetic distance (0–6 SNPs) between strains, deemed relapses, and three cases for which the genetic distance ranged from 1306 to 1419 SNPs, deemed re-infections. Six cases of relapse and six cases of mixed infection were classified differently by Whole-Genome Sequencing and MIRU-VNTR. We detected five single positive isolates (positive culture followed by at least two negative cultures) without clinical evidence of disease. Interpretation Whole-Genome Sequencing enables the differentiation of relapse and re-infection cases with greater resolution than do genotyping methods used at present, such as MIRU-VNTR, and provides insights into the biology of recurrence. The additional clarity provided by Whole-Genome Sequencing might have a role in defining endpoints for clinical trials. Funding Wellcome Trust, European Union, Medical Research Council, Global Alliance for TB Drug Development, European and Developing Country Clinical Trials Partnership.
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inferring patient to patient transmission of mycobacterium tuberculosis from Whole Genome Sequencing data
BMC Infectious Diseases, 2013Co-Authors: Josephine M Bryant, Simon R Harris, Anita C Schurch, Henk Van Deutekom, Jessica L De Beer, Victor De Jager, Kristin Kremer, Sacha A F T Van HijumAbstract:Background: Mycobacterium tuberculosis is characterised by limited genomic diversity, which makes the application of Whole Genome Sequencing particularly attractive for clinical and epidemiological investigation. However, in order to confidently infer transmission events, an accurate knowledge of the rate of change in the Genome over relevant timescales is required. Methods: We attempted to estimate a molecular clock by Sequencing 199 isolates from epidemiologically linked tuberculosis cases, collected in the Netherlands spanning almost 16 years. Results: Multiple analyses support an average mutation rate of ~0.3 SNPs per Genome per year. However, all analyses revealed a very high degree of variation around this mean, making the confirmation of links proposed by epidemiology, and inference of novel links, difficult. Despite this, in some cases, the phylogenetic context of other strains provided evidence supporting the confident exclusion of previously inferred epidemiological links. Conclusions: This in-depth analysis of the molecular clock revealed that it is slow and variable over short time scales, which limits its usefulness in transmission studies. However, the superior resolution of Whole Genome Sequencing can provide the phylogenetic context to allow the confident exclusion of possible transmission events previously inferred via traditional DNA fingerprinting techniques and epidemiological cluster investigation. Despite the slow generation of variation even at the Whole Genome level we conclude that the investigation of tuberculosis transmission will benefit greatly from routine Whole Genome Sequencing.
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Whole Genome Sequencing for analysis of an outbreak of meticillin resistant staphylococcus aureus a descriptive study
Lancet Infectious Diseases, 2013Co-Authors: Simon R Harris, Estee M Torok, Matthew J Ellington, Edward J. P. Cartwright, Michael A. Quail, Matthew T G Holden, Nick Brown, Amanda Ogilvystuart, Stephen D. BentleyAbstract:Summary Background The emergence of meticillin-resistant Staphylococcus aureus (MRSA) that can persist in the community and replace existing hospital-adapted lineages of MRSA means that it is necessary to understand transmission dynamics in terms of hospitals and the community as one entity. We assessed the use of Whole-Genome Sequencing to enhance detection of MRSA transmission between these settings. Methods We studied a putative MRSA outbreak on a special care baby unit (SCBU) at a National Health Service Foundation Trust in Cambridge, UK. We used Whole-Genome Sequencing to validate and expand findings from an infection-control team who assessed the outbreak through conventional analysis of epidemiological data and antibiogram profiles. We sequenced isolates from all colonised patients in the SCBU, and sequenced MRSA isolates from patients in the hospital or community with the same antibiotic susceptibility profile as the outbreak strain. Findings The hospital infection-control team identified 12 infants colonised with MRSA in a 6 month period in 2011, who were suspected of being linked, but a persistent outbreak could not be confirmed with conventional methods. With Whole-Genome Sequencing, we identified 26 related cases of MRSA carriage, and showed transmission occurred within the SCBU, between mothers on a postnatal ward, and in the community. The outbreak MRSA type was a new sequence type (ST) 2371, which is closely related to ST22, but contains genes encoding Panton-Valentine leucocidin. Whole-Genome Sequencing data were used to propose and confirm that MRSA carriage by a staff member had allowed the outbreak to persist during periods without known infection on the SCBU and after a deep clean. Interpretation Whole-Genome Sequencing holds great promise for rapid, accurate, and comprehensive identification of bacterial transmission pathways in hospital and community settings, with concomitant reductions in infections, morbidity, and costs. Funding UK Clinical Research Collaboration Translational Infection Research Initiative, Wellcome Trust, Health Protection Agency, and the National Institute for Health Research Cambridge Biomedical Research Centre.
James R Lupski - One of the best experts on this subject based on the ideXlab platform.
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Whole Genome Sequencing in a patient with charcot marie tooth neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, Claudia Gonzagajauregui, J G Reid, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Amy L McguireAbstract: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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Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
The New England Journal of Medicine, 2010Co-Authors: James R Lupski, Matthew N Bainbridge, David Rio Deiros, Lynne V Nazareth, Huyen Dinh, Chyn Jing, David A Wheeler, Jeffrey S. Reid, Claudia Gonzaga-jauregui, Amy L McguireAbstract: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.
