Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness
Ana Töpf, Katherine Johnson, Adam Bates, Lauren Phillips, Katherine R. Chao, Eleina England, Kristen M. Laricchia, T. Mullen, Elise Valkanas, Liwen Xu, Marta Bértoli, A. Blain, Ana Casasús, Jennifer Duff, Magdalena Mroczek, Sabine Specht, Monkol Lek, Monica Ensini, Daniel G. MacArthur, Ela Akay, Jorge Alonso‐Pérez, Jonathan Baets, Nina Barišić, Alexandra Bastian, S. Borell, Teodora Chamova, Kristl G. Claeys, Jaume Colomer, Sandra Coppens, Nicolas Deconinck, Willem De Ridder, Jordi Díaz‐Manera, Cristina Domínguez‐González, Alexis E. Duncan, Hacer Durmuş, Nagia Fahmy, Maria Elena Farrugia, Roberto Fernández‐Torrón, Lidia González‐Quereda, Jana Haberlová, Maja von der Hagen, Andreas Hahn, Antonia Jakovčević, Ivonne Jerico Pascual, Solange Kapetanovic, Viktorija Ķēniņa, Janbernd Kirschner, Andrea Klein, Heike Kölbel, Anna Kostera‐Pruszczyk, R. Kulshrestha, Jaana Lähdetie, Mahsa Layegh, Cheryl Longman, Adolfo López de Munaín, Wolfgang N. Löscher, Anna Łusakowska, Paul Maddison, Armelle Magot, Anirban Majumdar, Pilar Martí, Amaia Martínez Arroyo, Radim Mazanec, Sandra Mercier, Tiziana Mongini, Nuria Muelas, A. Nascimento, Shahriar Nafissi, Shirin Jamal Omidi, C. Ortez, Stéphanie Paquay, Yann Péréon, Stojan Perić, Valentina Ponzalino, Vidosava Rakočević Stojanović, Gauthier Remiche, Aida Rodríguez Sainz, Sabine Rudnik, I Sánchez Albisua, Manuela Santos, Ulrike Schara, Andriy Shatillo, Jadranka Sertić, Ulrich Stephani, Sonja Strang‐Karlsson, Yves Sznajer, Ani Tanev, Ivailo Tournev, Peter Van den Bergh, Vinciane Van Parijs, Juan J. Vílchez, Katharina Vill, John Vissing, Carina Wallgren‐Pettersson, Julia Wanschitz, Tracey Willis, Nanna Witting, Miren Zulaica, Volker Straub
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.