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Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

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@article{b79c728c7ea440579c4e121a5b61e39c,
title = "Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness",
abstract = "PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.RESULTS: We identified suspected pathogenic variants in 52{\%} of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48{\%}) need further investigation.CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.",
keywords = "genetic diagnosis, limb-girdle weakness, neuromuscular disease, next-generation sequencing, targeted exome analysis",
author = "Ana T{\"o}pf and Katherine Johnson and Adam Bates and Lauren Phillips and Chao, {Katherine R} and England, {Eleina M} and Laricchia, {Kristen M} and Thomas Mullen and Elise Valkanas and Liwen Xu and Marta Bertoli and Alison Blain and Casas{\'u}s, {Ana B} and Jennifer Duff and Magdalena Mroczek and Sabine Specht and Monkol Lek and Monica Ensini and MacArthur, {Daniel G} and Volker Straub and {MYO-SEQ consortium}",
year = "2020",
month = "9",
doi = "10.1038/s41436-020-0840-3",
language = "English",
volume = "22",
pages = "1478--1488",
journal = "Genetics In Medicine",
issn = "1098-3600",
publisher = "Lippincott Williams & Wilkins",
number = "9",

}

RIS

TY - JOUR

T1 - Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness

AU - Töpf, Ana

AU - Johnson, Katherine

AU - Bates, Adam

AU - Phillips, Lauren

AU - Chao, Katherine R

AU - England, Eleina M

AU - Laricchia, Kristen M

AU - Mullen, Thomas

AU - Valkanas, Elise

AU - Xu, Liwen

AU - Bertoli, Marta

AU - Blain, Alison

AU - Casasús, Ana B

AU - Duff, Jennifer

AU - Mroczek, Magdalena

AU - Specht, Sabine

AU - Lek, Monkol

AU - Ensini, Monica

AU - MacArthur, Daniel G

AU - Straub, Volker

AU - MYO-SEQ consortium

PY - 2020/9

Y1 - 2020/9

N2 - PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.RESULTS: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation.CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

AB - PURPOSE: Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology.METHODS: Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions.RESULTS: We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation.CONCLUSION: Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.

KW - genetic diagnosis

KW - limb-girdle weakness

KW - neuromuscular disease

KW - next-generation sequencing

KW - targeted exome analysis

UR - http://www.scopus.com/inward/record.url?scp=85086267166&partnerID=8YFLogxK

U2 - 10.1038/s41436-020-0840-3

DO - 10.1038/s41436-020-0840-3

M3 - Journal article

VL - 22

SP - 1478

EP - 1488

JO - Genetics In Medicine

JF - Genetics In Medicine

SN - 1098-3600

IS - 9

ER -

ID: 61073664