TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
14
11
2018
accepted:
03
12
2019
revised:
08
11
2019
pubmed:
4
1
2020
medline:
28
5
2021
entrez:
4
1
2020
Statut:
ppublish
Résumé
Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the DMD gene leading to the lack of dystrophin. Variability in the disease course suggests that other factors influence disease progression. With this study we aimed to identify genetic factors that may account for some of the variability in the clinical presentation. We compared whole-exome sequencing (WES) data in 27 DMD patients with extreme phenotypes to identify candidate variants that could affect disease progression. Validation of the candidate SNPs was performed in two independent cohorts including 301 (BIO-NMD cohort) and 109 (CINRG cohort of European ancestry) DMD patients, respectively. Variants in the Tctex1 domain containing 1 (TCTEX1D1) gene on chromosome 1 were associated with age of ambulation loss. The minor alleles of two independent variants, known to affect TCTEX1D1 coding sequence and induce skipping of its exon 4, were associated with earlier loss of ambulation. Our data show that disease progression of DMD is affected by a new locus on chromosome 1 and demonstrate the possibility to identify genetic modifiers in rare diseases by studying WES data in patients with extreme phenotypes followed by multiple layers of validation.
Identifiants
pubmed: 31896777
doi: 10.1038/s41431-019-0563-6
pii: 10.1038/s41431-019-0563-6
pmc: PMC7253478
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
815-825Subventions
Organisme : EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)
ID : 305444
Pays : International
Organisme : Association Française contre les Myopathies (French Association against Muscular Dystrophies)
ID : 17724
Pays : International
Organisme : EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)
ID : 305121
Pays : International
Organisme : EC | EC Seventh Framework Programm | FP7 Health (FP7-HEALTH - Specific Programme "Cooperation": Health)
ID : 241665
Pays : International
Organisme : NIAMS NIH HHS
ID : R01 AR061875
Pays : United States
Organisme : U.S. Department of Education (ED)
ID : #H133B090001
Pays : International
Organisme : Association Française contre les Myopathies (French Association against Muscular Dystrophies)
ID : 17013
Pays : International
Organisme : U.S. Department of Education (ED)
ID : #H133B031118
Pays : International
Organisme : U.S. Department of Defense (United States Department of Defense)
ID : W81XWH-12-1-0417
Pays : International
Investigateurs
Alberto Dubrovsky
(A)
Andrew Kornberg
(A)
Kathryn North
(K)
Monique Ryan
(M)
Richard Webster
(R)
W Douglas Biggar
(WD)
Laura C McAdam
(LC)
Jean K Mah
(JK)
Hanna Kolski
(H)
V Vishwanathan
(V)
S Chidambaranathan
(S)
Yoram Nevo
(Y)
Ksenija Gorni
(K)
Jose Carlo
(J)
Mar Tulinius
(M)
Timothy Lotze
(T)
Tulio E Bertorini
(TE)
John W Day
(JW)
Peter Karachunski
(P)
Paula R Clemens
(PR)
Hoda Abdel-Hamid
(H)
Jean Teasley
(J)
Nancy Kuntz
(N)
Sherilyn Driscoll
(S)
John B Bodensteiner
(JB)
Anne M Connolly
(AM)
Alan Pestronk
(A)
R T Abresch
(RT)
Erik K Henricson
(EK)
Nanette C Joyce
(NC)
Craig M McDonald
(CM)
Avital Cnaan
(A)
Heather Gordish-Dressmsn
(H)
Lauren P Morgenroth
(LP)
Robert Leshner
(R)
Carolina Tesi-Rocha
(C)
Mathula Thangarajh
(M)
Tina Duong
(T)
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