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

被引：574

作者：

Bladen, Catherine L. ^{[1
]}

Salgado, David ^{[2
]}

Monges, Soledad ^{[3
]}

Foncuberta, Maria E. ^{[3
]}

Kekou, Kyriaki ^{[4
]}

Kosma, Konstantina ^{[4
,5
]}

Dawkins, Hugh ^{[6
]}

Lamont, Leanne ^{[6
]}

Roy, Anna J. ^{[7
]}

Chamova, Teodora ^{[8
]}

Guergueltcheva, Velina ^{[8
]}

Chan, Sophelia ^{[9
]}

Korngut, Lawrence ^{[10
,11
]}

Campbell, Craig ^{[12
]}

Dai, Yi ^{[13
,14
]}

Wang, Jen ^{[15
]}

Barisic, Nina ^{[16
]}

Brabec, Petr ^{[17
]}

Lahdetie, Jaana ^{[18
]}

Walter, Maggie C. ^{[19
]}

Schreiber-Katz, Olivia ^{[19
]}

Karcagi, Veronika ^{[20
]}

Garami, Marta ^{[20
]}

Viswanathan, Venkatarman ^{[21
,22
]}

Bayat, Farhad ^{[23
]}

Buccella, Filippo ^{[24
]}

Kimura, En

Koeks, Zaida ^{[25
]}

van den Bergen, Janneke C. ^{[25
]}

Rodrigues, Miriam ^{[26
]}

Roxburgh, Richard ^{[26
]}

Lusakowska, Anna ^{[27
]}

Kostera-Pruszczyk, Anna ^{[27
]}

Zimowski, Janusz ^{[28
]}

Santos, Rosario ^{[29
]}

Neagu, Elena ^{[30
]}

Artemieva, Svetlana ^{[31
]}

Rasic, Vedrana Milic ^{[32
]}

Vojinovic, Dina ^{[32
]}

Posada, Manuel ^{[33
,34
]}

Bloetzer, Clemens ^{[35
]}

Jeannet, Pierre-Yves ^{[35
]}

Joncourt, Franziska ^{[36
]}

Diaz-Manera, Jordi ^{[37
]}

Gallardo, Eduard ^{[37
]}

Karaduman, A. Ayse ^{[38
]}

Topaloglu, Haluk ^{[39
]}

El Sherif, Rasha ^{[40
]}

Stringer, Angela ^{[41
]}

Shatillo, Andriy V. ^{[42
]}

机构：

[1] Univ Newcastle, Inst Med Genet, John Walton Muscular Dystrophy Res Ctr, MRC Ctr Neuromuscular Dis, Newcastle Upon Tyne NE13BZ, Tyne & Wear, England

[2] Aix Marseille Univ, INSERM, GMGF UMR S 910, Marseille, France

[3] Hosp Pediat JP Garrahan, Pichincha, Argentina

[4] Univ Athens, Sch Med, Dept Med Genet, GR-11527 Athens, Greece

[5] St Sophias Childrens Hosp Thinon & Levadia Goudi, Choremio Res Lab, Athens, Greece

[6] Off Populat Hlth Genom, Dept Hlth, Perth, WA, Australia

[7] WIV ISP, Brussels, Belgium

[8] Med Univ Sofia, Dept Neurol, Sofia, Bulgaria

[9] Univ Hong Kong, Queen Mary Hosp, Dept Paediat & Adolescent Med, Pok Fu Lam, Hong Kong, Peoples R China

[10] Univ Calgary, Dept Clin Neurosci, Calgary, AB, Canada

[11] Univ Calgary, Hotchkiss Brain Inst, Calgary, AB, Canada

[12] Univ Western Ontario, Dept Paediat Clin Neurol Sci & Epidemiol, London, ON, Canada

[13] Peking Union Med Coll, Dept Neurol, Peking Union Med Coll Hosp, Beijing 100021, Peoples R China

[14] Chinese Acad Med Sci, Beijing 100730, Peoples R China

[15] China Dolls, Dept Neurol, Beijing, Peoples R China

[16] Univ Zagreb, Sch Med, Univ Hosp Ctr Zagreb KBC Zagreb, Div Paediat Neurol, Zagreb 41000, Croatia

[17] Masaryk Univ, Inst Biostat & Anal, Brno, Czech Republic

[18] Turku Univ, Cent Hosp, Dept Child Neurol, Turku, Finland

[19] Univ Munich, Friedrich Baur Inst, Dept Neurol, Munich, Germany

[20] NIEH, Dept Mol Genet & Diagnost, Budapest, Hungary

[21] CHILDS Trust Med Res Fdn, Madras, Tamil Nadu, India

[22] Apollo Childrens Hosp, Madras, Tamil Nadu, India

[23] Pasteur Inst Iran, Tehran, Iran

[24] Parent Project Onlus, Rome, Italy

[25] Leiden Univ, Dept Neurol, Med Ctr, Leiden, Netherlands

[26] Auckland DHB, Dept Neurol, Auckland, New Zealand

[27] Med Univ Warsaw, Dept Neurol, Warsaw, Poland

[28] Inst Psychiat & Neurol, Dept Genet, Warsaw, Poland

[29] Ctr Genet Med Jacinto Magalhaes, Oporto, Portugal

[30] Natl Inst Legal Med, Genet Lab, Bucharest, Romania

[31] Moscow Inst Pediat, Moscow, Russia

[32] Univ Belgrade, Fac Med, Clin Neurol & Psychiat Children & Youth, Belgrade, Serbia

[33] Inst Hlth Carlos III, Inst Rare Dis Res, Spain RDR, Madrid, Spain

[34] Inst Hlth Carlos III, CIBERER, Madrid, Spain

[35] Univ Lausanne Hosp, Neurorehabil Unit, Lausanne, Switzerland

[36] Univ Bern, Inselspital, Div Human Genet, Childrens Univ Hosp, CH-3010 Bern, Switzerland

[37] Hosp Santa CreuiSt Pau Barcelona, Serv Neurol, Unitat MalaltiesNeuromusculars, Barcelona, Spain

[38] Hacettepe Univ, Fac Hlth Sci, Dept Physiotherapy & Rehabil, Ankara, Turkey

[39] Hacettepe Childrens Hosp Med Ctr, Ankara, Turkey

[40] Ain Shams Univ, Egypt Air Hosp, Neurol & Neurogen Unit, Cairo, Egypt

[41] Epictr, Act Duchenne, London, England

[42] NAMS, Psychiat & Narcol, Inst Neurol, Kharkov, Ukraine

[43] Duchenne Connect, Hackensack, NJ USA

[44] Murdoch Univ, Ctr Comparat Gen, Murdoch, WA 6150, Australia

[45] Univ Med Ctr Freiburg, Freiburg, Germany

[46] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH USA

[47] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands

[48] Hop Enfants La Timone, INSERM, APHM, Dept Genet Med & Biol Cellulaire, F-13385 Marseille, France

来源：

HUMAN MUTATION | 2015年 / 36卷 / 04期

关键词：

DMD; Duchenne muscular dystrophy; TREAT-NMD; rare disease registries; NONSENSE MUTATIONS; MUSCLE-CELLS; EXON; RECOMMENDATIONS; EXPRESSION; PHENOTYPE; PTC124; MODEL; ACIDS;

D O I：

10.1002/humu.22758

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

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 (). 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).

引用

页码：395 / 402

页数：8

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