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

Lookup NU author(s): Dr Ana TopfORCiD, Dr Katherine JohnsonORCiD, Adam Bates, Lauren Charlotte Phillips Phillips, Dr Marta Bertoli, Dr Alison Blain, Ana Belen Casasus Tomas, Dr Jennifer Duff, Magdalena Mroczek, Dr Sabine Specht, Dr Monica Ensini, Dr Hacer Durmus, Roberto Fernandez-Torron, Dr Jana Haberlova, Dr Tracey Willis, Professor Volker StraubORCiD



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2020, The Author(s). 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.

Publication metadata

Author(s): Topf A, Johnson K, Bates A, Phillips L, Chao KR, England EM, Laricchia KM, Mullen T, Valkanas E, Xu L, Bertoli M, Blain A, Casasus AB, Duff J, Mroczek M, Specht S, Lek M, Ensini M, MacArthur DG, Akay E, Alonso-Perez J, Baets J, Barisic N, Bastian A, Borell S, Chamova T, Claeys K, Colomer J, Coppens S, Deconinck N, de Ridder W, Diaz-Manera J, Dominguez-Gonzalez C, Duncan A, Durmus H, Fahmy NA, Farrugia ME, Fernandez-Torron R, Gonzalez-Quereda L, Haberlova J, von der Hagen M, Hahn A, Jakovcevic A, JericoPascual I, Kapetanovic S, Kenina V, Kirschner J, Klein A, Kolbel H, Kostera-Pruszczyk A, Kulshrestha R, Lahdetie J, Layegh M, Longman C, Lopezde Munain A, Loscher W, Lusakowska A, Maddison P, Magot A, Majumdar A, Marti P, MartinezArroyo A, Mazanec R, Mercier S, Mongini T, Muelas N, Nascimento A, Nafissi S, Omidi S, Ortez C, Paquay S, Pereon Y, Peric S, Ponzalino V, Rakocevic Stojanovic V, Remiche G, RodriguezSainz A, Rudnik S, SanchezAlbisua I, Santos M, Schara U, Shatillo A, Sertic J, Stephani U, Strang-Karlsson S, Sznajer Y, Tanev A, Tournev I, Van den Bergh P, Van Parijs V, Vilchez J, Vill K, Vissing J, Wallgren-Pettersson C, Wanschitz J, Willis T, Witting N, Zulaica M, Straub V

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2020

Volume: 22

Pages: 1478-1488

Print publication date: 01/09/2020

Online publication date: 11/06/2020

Acceptance date: 08/05/2020

Date deposited: 10/07/2020

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Springer Nature


DOI: 10.1038/s41436-020-0840-3


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Funder referenceFunder name
... Muscular Dystrophy UK, and Coalition to Cure Calpain 3.
National Heart, Lung, and Blood Institute grant UM1 HG008900,
National Human Genome Research Institute, the National Eye Institute,
MYO-SEQ was funded by Sanofi Genzyme, Ultragenyx, LGMD2I Research Fund, Samantha J. Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation, ...
National Human Genome Research Institute grant R01 HG009141.