TY - JOUR
T1 - TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy
AU - CINRG Investigators
AU - Spitali, Pietro
AU - Zaharieva, Irina
AU - Bohringer, Stefan
AU - Hiller, Monika
AU - Chaouch, Amina
AU - Roos, Andreas
AU - Scotton, Chiara
AU - Claustres, Mireille
AU - Bello, Luca
AU - McDonald, Craig M.
AU - Hoffman, Eric P.
AU - Dubrovsky, Alberto
AU - Kornberg, Andrew
AU - North, Kathryn
AU - Ryan, Monique
AU - Webster, Richard
AU - Biggar, W. Douglas
AU - McAdam, Laura C.
AU - Mah, Jean K.
AU - Kolski, Hanna
AU - Vishwanathan, V.
AU - Chidambaranathan, S.
AU - Nevo, Yoram
AU - Gorni, Ksenija
AU - Carlo, Jose
AU - Tulinius, Mar
AU - Lotze, Timothy
AU - Bertorini, Tulio E.
AU - Day, John W.
AU - Karachunski, Peter
AU - Clemens, Paula R.
AU - Abdel-Hamid, Hoda
AU - Teasley, Jean
AU - Kuntz, Nancy
AU - Driscoll, Sherilyn
AU - Bodensteiner, John B.
AU - Connolly, Anne M.
AU - Pestronk, Alan
AU - Abresch, R. T.
AU - Henricson, Erik K.
AU - Joyce, Nanette C.
AU - Cnaan, Avital
AU - Gordish-Dressmsn, Heather
AU - Morgenroth, Lauren P.
AU - Leshner, Robert
AU - Tesi-Rocha, Carolina
AU - Thangarajh, Mathula
AU - Duong, Tina
AU - Koeks, Zaida
AU - Eka Suchiman, H.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85078213568&partnerID=8YFLogxK
U2 - 10.1038/s41431-019-0563-6
DO - 10.1038/s41431-019-0563-6
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C2 - 31896777
AN - SCOPUS:85078213568
SN - 1018-4813
VL - 28
SP - 815
EP - 825
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 6
ER -