Spitali, Pietro ORCID: 0000-0003-2783-688X, Zaharieva, Irina, Bohringer, Stefan, Hiller, Monika, Chaouch, Amina, Roos, Andreas, Scotton, Chiara, Claustres, Mireille, Bello, Luca ORCID: 0000-0002-3075-6525, McDonald, Craig M., Hoffman, Eric P., Koeks, Zaida, Suchiman, H. Eka, Cirak, Sebahattin, Scoto, Mariacristina, Reza, Mojgan, 't Hoen, Peter A. C., Niks, Erik H., Tuffery-Giraud, Sylvie, Lochmueller, Hanns, Ferlini, Alessandra, Muntoni, Francesco, Aartsma-Rus, Annemieke, Dubrovsky, Alberto, Kornberg, Andrew, North, Kathryn, Ryan, Monique, Webster, Richard, Biggar, W. Douglas, McAdam, Laura C., Mah, Jean K., Kolski, Hanna, Vishwanathan, V., Chidambaranathan, S., Nevo, Yoram, Gorni, Ksenija, Carlo, Jose, Tulinius, Mar, Lotze, Timothy, Bertorini, Tulio E., Day, John W., Karachunski, Peter, Clemens, Paula R., Abdel-Hamid, Hoda, Teasley, Jean, Kuntz, Nancy, Driscoll, Sherilyn, Bodensteiner, John B., Connolly, Anne M., Pestronk, Alan, Abresch, R. T., Henricson, Erik K., Joyce, Nanette C., Cnaan, Avital, Gordish-Dressmsn, Heather, Morgenroth, Lauren P., Leshner, Robert, Tesi-Rocha, Carolina, Thangarajh, Mathula and Duong, Tina (2020). TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy. Eur. J. Hum. Genet., 28 (6). S. 815 - 826. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5438

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Spitali, PietroUNSPECIFIEDorcid.org/0000-0003-2783-688XUNSPECIFIED
Zaharieva, IrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bohringer, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hiller, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chaouch, AminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roos, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scotton, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claustres, MireilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bello, LucaUNSPECIFIEDorcid.org/0000-0002-3075-6525UNSPECIFIED
McDonald, Craig M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman, Eric P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koeks, ZaidaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Suchiman, H. EkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scoto, MariacristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reza, MojganUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
't Hoen, Peter A. C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niks, Erik H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuffery-Giraud, SylvieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lochmueller, HannsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferlini, AlessandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muntoni, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aartsma-Rus, AnnemiekeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dubrovsky, AlbertoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kornberg, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
North, KathrynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ryan, MoniqueUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Webster, RichardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Biggar, W. DouglasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McAdam, Laura C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mah, Jean K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolski, HannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vishwanathan, V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chidambaranathan, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nevo, YoramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorni, KsenijaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carlo, JoseUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tulinius, MarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lotze, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bertorini, Tulio E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Day, John W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karachunski, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clemens, Paula R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abdel-Hamid, HodaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teasley, JeanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuntz, NancyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Driscoll, SherilynUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bodensteiner, John B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Connolly, Anne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pestronk, AlanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abresch, R. T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henricson, Erik K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joyce, Nanette C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cnaan, AvitalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gordish-Dressmsn, HeatherUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgenroth, Lauren P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leshner, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tesi-Rocha, CarolinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thangarajh, MathulaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duong, TinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-349337
DOI: 10.1038/s41431-019-0563-6
Journal or Publication Title: Eur. J. Hum. Genet.
Volume: 28
Number: 6
Page Range: S. 815 - 826
Date: 2020
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1476-5438
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
6-MINUTE WALK TEST; NATURAL-HISTORY; END-POINTS; ASSOCIATION; EXPRESSION; VARIANTS; PATHWAYS; GENOTYPE; DATABASEMultiple languages
Biochemistry & Molecular Biology; Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/34933

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