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

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Töpf A.
  • Johnson K.
  • Bates A.
  • Phillips L.
  • Chao K.R.
  • England E.M.
  • Laricchia K.M.
  • Mullen T.
  • Valkanas E.
  • Xu L.
  • Bertoli M.
  • Blain A.
  • Casasús A.B.
  • Duff J.
  • Mroczek M.
  • Specht S.
  • Lek M.
  • Ensini M.
  • MacArthur D.G.
  • Akay E.
  • Alonso-Pérez J.
  • Baets J.
  • Barisic N.
  • Bastian A.
  • Borell S.
  • Chamova T.
  • Claeys K.
  • Colomer J.
  • Coppens S.
  • Deconinck N.
  • de Ridder W.
  • Díaz-Manera J.
  • Domínguez-González C.
  • Duncan A.
  • Durmus H.
  • Fahmy N.A.
  • Farrugia M.E.
  • Fernández-Torrón R.
  • Gonzalez-Quereda L.
  • Haberlova J.
  • von der Hagen M.
  • Hahn A.
  • Jakovcevic A.
  • Jerico Pascual I.
  • Kapetanovic S.
  • Kenina V.
  • Kirschner J.
  • Klein A.
  • Kölbel H.
  • Kostera-Pruszczyk A.
  • Kulshrestha R.
  • Lähdetie J.
  • Layegh M.
  • Longman C.
  • López de Munain A.
  • Loscher W.
  • Lusakowska A.
  • Maddison P.
  • Magot A.
  • Majumdar A.
  • Martínez Arroyo A.
  • Mazanec R.
  • Mercier S.
  • Mongini T.
  • Nascimento A.
  • Nafissi S.
  • Omidi S.
  • Ortez C.
  • Paquay S.
  • Pereon Y.
  • Peric S.
  • Ponzalino V.
  • Rakocevic Stojanovic V.
  • Remiche G.
  • Rodríguez Sainz A.
  • Rudnik S.
  • Sanchez Albisua 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.
  • Vílchez J.
  • Vill K.
  • Vissing J.
  • Wallgren-Pettersson C.
  • Wanschitz J.
  • Willis T.
  • Witting N.
  • Zulaica M.
  • Straub V.

Grupos

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. © 2020, The Author(s).

Datos de la publicación

ISSN/ISSNe:
1098-3600, 1530-0366

GENETICS IN MEDICINE  ELSEVIER SCIENCE INC

Tipo:
Article
Páginas:
1478-1488
PubMed:
32528171
Enlace a otro recurso:
www.scopus.com
Factor de Impacto:
3,509 SCImago ℠
Cuartil:
Q1 SCImago ℠

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Keywords

  • Anoctamins; Exome; Glucosyltransferases; Humans; Muscular Dystrophies, Limb-Girdle; Whole Exome Sequencing; creatine kinase; ANO5 protein, human; anoctamin; glucosyltransferase; POGLUT1 protein, human; adult; ANO5 gene; Article; autosomal dominant inheritance; BVES gene; CAPN3 gene; COL6A2 gene; controlled study; DMD gene; DYSF gene; female; gene; heterozygosity; homozygosity; human; indel mutation; major clinical study; male; muscle weakness; neuromuscular disease; POGLUT1 gene; RYR1 gene; SGCA gene; single nucleotide polymorphism; targeted exome sequencing; TTN gene; whole exome sequencing; exome; genetics; limb girdle muscular dystrophy; whole exome sequencing

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