Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness
Töpf, Ana (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Johnson, Katherine (Newcastle University)
Bates, Adam (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Phillips, Lauren (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Chao, Katherine R. (Broad Institute of MIT and Harvard)
England, Eleina M. (Broad Institute of MIT and Harvard)
Laricchia, KristenM. (Broad Institute of MIT and Harvard)
Mullen, Thomas (Broad Institute of MIT and Harvard)
Valkanas, Elise (Broad Institute of MIT and Harvard)
Xu, Liwen (Broad Institute of MIT and Harvard)
Bertoli, Marta (Newcastle upon Tyne NHS Foundation Trust)
Blain, Alison (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Casasús, Ana B. (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Duff, Jennifer (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Mroczek, Magdalena (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Specht, Sabine (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Lek, Monkol (Yale University School of Medicine)
Ensini, Monica (Directorate E. Unit E2 Combatting Diseases)
MacArthur, Daniel G. (Murdoch Children's Research Institute)
Akay, Ela (Newcastle upon Tyne Hospitals NHS Foundation Trust)
Alonso-Pérez, Jorge (Institut d'Investigació Biomèdica Sant Pau)
Baets, Jonathan (University of Antwerp)
Barisic, Nina (Zagreb Medical School)
Bastian, Alexandra (University of Medicine and Pharmacy Carol Davila Bucharest)
Borell, Sabine (University of Freiburg)
Chamova, Teodora (Alexandrovska Medical University)
Claeys, Kristl (KU Leuven)
Colomer, Jaume (Hospital Sant Joan de Deu)
Coppens, Sandra (Université Libre de Bruxelles)
Deconinck, Nicolas (Hôpital Universitaire des Enfants Reine Fabiola (HUDERF))
de Ridder, Willem (University of Antwerp)
Diaz-Manera, Jordi (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Domínguez-González, C (Instituto de Investigación Hospital 12 de Octubre Centro de Actividades Ambulatorias)
Duncan, Alexis (Queen Elizabeth University Hospital)
Durmus, Hacer (Istanbul Faculty of Medicine)
Fahmy, Nagia A. (Ain Shams University (El Caire, Egipte))
Farrugia, Maria Elena (Queen Elizabeth University Hospital)
Fernández-Torrón, Roberto (Instituto de Salud Carlos III)
Gonzalez-Quereda, L (Institut d'Investigació Biomèdica Sant Pau)
Haberlova, Jana (Charles University)
von der Hagen, Maja (Technische Universität Dresden)
Hahn, Andreas (Justus-Liebig-University Giessen)
Jakovčević, Antonia (School of Medicine Zagreb)
Jerico Pascual, Ivonne (Complejo Hospitalario de Navarra)
Kapetanovic, Solange (Hospital de Basurto (Bilbao, Biscaia))
Kenina, Viktorija (Riga East University Hospital)
Kirschner, Janbernd (University of Freiburg)
Klein, Andrea (Inselspital Bern)
Kölbel, Heike (University of Duisburg)
Kostera-Pruszczyk, Anna (Medical University of Warsaw)
Kulshrestha, Richa (RJAH Orthopaedic Hospital NHS Foundation Trust)
Lähdetie, Jaana (University of Turku and Turku University Central Hospital)
Layegh, Mahsa (Tehran University of Medical Sciences)
Longman, Cheryl (Queen Elizabeth University Hospital)
López de Munain, Adolfo (University of the Basque Country UPV-EHU)
Loscher, Wolfgang (Medical University of Innsbruck)
Lusakowska, Anna (Medical University of Warsaw)
Maddison, Paul (Nottingham University Hospitals NHS Trust (Regne Unit))
Magot, Armelle (Hôtel-Dieu. University Hospital)
Majumdar, Anirban (Bristol Children's Hospital)
Martí, Pilar (Instituto de Investigación Sanitaria La Fe)
Martínez Arroyo, Amaia (Hospital Galdakao)
Mazanec, Radim (Charles University)
Mercier, Sandra (Hôtel-Dieu. University Hospital)
Mongini, Tiziana (University of Turin)
Muelas, Nuria (Instituto de Investigación Sanitaria La Fe)
Nascimento, Andrés (Hospital Sant Joan de Deu)
Nafissi, Shahriar (Tehran University of Medical Sciences)
Omidi, Shirin (Tehran University of Medical Sciences)
Ortez González, Carlos Ignacio (Hospital Sant Joan de Déu (Barcelona, Catalunya))
Paquay, Stéphanie (Université de Louvain)
Pereon, Yann (Hôtel-Dieu. University Hospital)
Perić, Stojan (Clinical Center of Serbia)
Ponzalino, Valentina (University of Turin)
Rakočević Stojanović, Vidosava (Clinical Center of Serbia)
Remiche, Gauthier (Université Libre de Bruxelles)
Rodríguez Sainz, Aida (Hospital Galdakao)
Rudnik, Sabine (Medical University Innsbruck)
Sanchez Albisua, Iciar (University of Tübingen)
Santos, Manuela (Centro Hospitalar Universitário Porto)
Schara, Ulrike (University of Duisburg)
Shatillo, Andriy (Psychiatry and Narcology of NAMS of Ukraine)
Sertić, Jadranka (Zagreb Medical School)
Stephani, Ulrich (University Medical Center Schleswig-Holstein)
Strang-Karlsson, Sonja (Helsinki University Hospital)
Sznajer, Yves (Université de Louvain)
Tanev, Ani (Alexandrovska Medical University)
Tournev, Ivailo (New Bulgarian University)
Van den Bergh, Peter (Université de Louvain)
Van Parijs, Vinciane (Université de Louvain)
Vílchez, Juan (Instituto de Investigación Sanitaria La Fe)
Vill, Katharina (Dr. v. Hauner Children's Hospital)
Vissing, John (University of Copenhagen)
Wallgren-Pettersson, Carina (University of Helsinki)
Wanschitz, Julia (Medical University of Innsbruck)
Willis, Tracey (RJAH Orthopaedic Hospital NHS Foundation Trust)
Witting, Nanna (University of Copenhagen)
Zulaica, Miren (Hospital de Donostia (Sant Sebastià, País Basc))
Straub, Volker (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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. 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. 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. 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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Genetic diagnosis ; Limb-girdle weakness ; Neuromuscular disease ; Next-generation sequencing ; Targeted exome analysis
Publicat a:	Genetics in medicine, Vol. 22 Núm. 9 (january 2020) , p. 1478-1488, ISSN 1530-0366

DOI: 10.1038/s41436-020-0840-3
PMID: 32528171

11 p, 1.1 MB

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