The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations

Catherine Bladen , David Salgado (1) , Soledad Monges (2) , Maria E Foncuberta , Kyriaki Kekou , Konstantina Kosma , Hugh Dawkins (3) , Leanne Lamont , Anna Roy , Teodora Chamova , Velina Guergueltcheva , Sophelia Chan , Lawrence Korngut , Craig Campbell , Yi Dai , Jen Wang , Nina Barišić , Petr Brabec , Jaana Lahdetie , Maggie C Walter (4) , Olivia Schreiber-Katz , Veronika Karcagi , Marta Garami , Venkatarman Viswanathan , Farhad Bayat , Filippo Buccella , En Kimura , Zaïda Koeks , Jan van den Bergen , Miriam Rodrigues , Richard Roxburgh , Anna Lusakowska (5) , Anna Kostera-Pruszczyk , Jan Zimowski , Rosário Santos , Elena Neagu , Svetlana Artemieva , Vedrana Milic Rasic , Dina Vojinovic , Manuel Posada (6) , Clemens Bloetzer , Pierre-Yves Jeannet , Franziska Joncourt , Jordi Díaz-Manera , Eduard Gallardo , a Ayşe Karaduman , Haluk Topaloğlu , Rasha El Sherif , Angela Stringer , Andriy V Shatillo , Ann S Martin , Holly L Peay , Matthew I Bellgard , Jan Kirschner , Kevin M Flanigan , Volker Straub (7) , Kate Bushby (7) , Jan Verschuuren , Annemieke Aartsma-Rus (8) , Christophe Béroud (1) , Hanns Lochmuller (9) , Maria E. Foncuberta , Maggie C. Walter , A. Ayşe Karaduman , Andriy V. Shatillo , Ann S. Martin , Holly L. Peay , Matthew I. Bellgard , Kevin M. Flanigan

1 GMGF - Génétique Médicale et Génomique Fonctionnelle
2 Neuropaediatrics
3 Centre for Comparative Genomics
4 Department of Biological and Environmental Engineering
5 Department of Embryology [Warsaw]
6 Medicina Pediátrica y del Desarrollo
7 Department of Neurology
8 Human Genetics
9 Newcastle University [Newcastle]

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).

Mots clés: DMD; Duchenne muscular dystrophy; TREAT-NMD; rare disease registries

Domaines: Bio-informatique [q-bio.QM]; Génétique humaine; Biologie moléculaire

Catherine Bladen, David Salgado, Soledad Monges, Maria E Foncuberta, Kyriaki Kekou, et al.. The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations. Human Mutation, 2015, 36 (4), pp.395 - 402. ⟨10.1002/humu.22758⟩. ⟨hal-01681769⟩