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1. TCTEX1D1 is a genetic modifier of disease progression in Duchenne muscular dystrophy.

Author

Spitali, Pietro, Zaharieva, Irina, Bohringer, Stefan, Hiller, Monika, Chaouch, Amina, Roos, Andreas, Scotton, Chiara, Claustres, Mireille, Bello, Luca, Hoffman, Eric, Koeks, Zaida, Eka Suchiman, H, Cirak, Sebahattin, Scoto, Mariacristina, Reza, Mojgan, t Hoen, Peter, Niks, Erik, Tuffery-Giraud, Sylvie, Lochmüller, Hanns, Ferlini, Alessandra, Muntoni, Francesco, Aartsma-Rus, Annemieke, and McDonald, Craig

Subjects
Adolescent, Child, Disease Progression, Genes, Modifier, Humans, Male, Muscular Dystrophy, Duchenne, Phenotype, Polymorphism, Single Nucleotide
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.

Published
2020

2. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

Author

Janine Altmüller, Stefan Böhringer, G. Eda Utine, Krystyna H. Chrzanowska, Peter Nürnberg, Maria Teresa Dotti, Marcel Martin, Holger Thiele, Johanna Christina Czeschik, Esra Kılıç, Gunnar Houge, Almuth Caliebe, Sigrid Tinschert, Koray Boduroğlu, Yun Li, Francesca Cristofoli, Filippo Beleggia, Fanny Morice-Picard, Christiane Zweier, Michèle Mathieu Dramard, Joris Vermeesch, Małgorzata Krajewska-Walasek, Beate Albrecht, Hermann-Josef Lüdecke, Ozgur Cogulu, Yasemin Alanay, Annabella Marozza, Hülya Kayserili, Timm O. Goecke, Koenraad Devriendt, Bernd Wollnik, Catheline Vilain, Pelin Ozlem Simsek-Kiper, Esther Pohl, Anita Rauch, Barbara Mikat, Michael Zeschnigk, Nursel Elcioglu, R. Vivarelli, Joussef Hayek, Alma Kuechler, Stanislas Lyonnet, Esther Milz, Dagmar Wieczorek, Sven Rahmann, Encarnación Guillén-Navarro, Blanca Gener, Ludger Klein-Hitpass, Nina Bögershausen, Gilles Morin, Ferda Ozkinay, Alessandra Renieri, Vanesa López-González, Sabine Steiner-Haldenstätt, Andreas Wollstein, Francesca Mari, İç Hastalıkları, Acibadem University Dspace, Wieczorek, Dagmar, Boegershausen, Nina, Beleggia, Filippo, Steiner-Haldenstaett, Sabine, Pohl, Esther, Li, Yun, Milz, Esther, Martin, Marcel, Thiele, Holger, Altmueller, Janine, Alanay, Yasemin, Kayserili, Hulya, Klein-Hitpass, Ludger, Bohringer, Stefan, Wollstein, Andreas, Albrecht, Beate, Boduroglu, Koray, Caliebe, Almuth, Chrzanowska, Krystyna, Cogulu, Ozgur, Cristofoli, Francesca, Czeschik, Johanna Christina, Devriendt, Koenraad, Dotti, Maria Teresa, Elcioglu, Nursel, Gener, Blanca, Goecke, Timm O., Krajewska-Walasek, Malgorzata, Guillen-Navarro, Encarnacion, Hayek, Joussef, Houge, Gunnar, Kilic, Esra, Simsek-Kiper, Pelin Ozlem, Lopez-Gonzalez, Vanesa, Kuechler, Alma, Lyonnet, Stanislas, Mari, Francesca, Marozza, Annabella, Dramard, Michele Mathieu, Mikat, Barbara, Morin, Gilles, Morice-Picard, Fanny, Ozkinay, Ferda, Rauch, Anita, Renieri, Alessandra, Tinschert, Sigrid, Utine, G. Eda, Vilain, Catheline, Vivarelli, Rossella, Zweier, Christiane, Nuernberg, Peter, Rahmann, Sven, Vermeesch, Joris, Luedecke, Hermann-Josef, Zeschnigk, Michael, Wollnik, Bernd, Ege Üniversitesi, and University of Zurich

Subjects
Male, ARID1A, 10039 Institute of Medical Genetics, Chromosomal Proteins, Non-Histone, PHF6, Medizin, Hypotrichosis, Missense mutation, Exome, FORSSMAN-LEHMANN-SYNDROME, INTELLECTUAL DISABILITY, MENTAL-RETARDATION, MUTATIONS, SWI/SNF, COMPLEX, COMPONENTS, ARID1B, SMARCB1, Child, Genetics (clinical), Sequence Deletion, Genetics, Genetics & Heredity, biology, High-Throughput Nucleotide Sequencing, General Medicine, SMARCB1 Protein, Phenotype, Chromatin, DNA-Binding Proteins, Histone, Child, Preschool, Female, Hand Deformities, Congenital, Adult, 2716 Genetics (clinical), Biochemistry & Molecular Biology, Adolescent, Foot Deformities, Congenital, Micrognathism, Mutation, Missense, 610 Medicine & health, Chromatin remodeling, 1311 Genetics, Intellectual Disability, 1312 Molecular Biology, Nucleosome, Humans, Abnormalities, Multiple, Molecular Biology, Infant, Newborn, Facies, Infant, Chromatin Assembly and Disassembly, Repressor Proteins, Face, Karyotyping, biology.protein, 570 Life sciences, Carrier Proteins, Neck, Transcription Factors
Abstract

WOS: 000327800400004, PubMed ID: 23906836, Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-Siris (CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation ( NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6. We show that mutations in ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies., German Federal Ministry of Education and Research (BMBF)Federal Ministry of Education & Research (BMBF) [01GM1211A, 01GM1211B]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [112S398]; ERARE-ANR CraniRareFrench National Research Agency (ANR); German Federal Ministry of Education and ResearchFederal Ministry of Education & Research (BMBF) [01GS08167]; DFGGerman Research Foundation (DFG) [BO 1955/2-3, WU 314/6-2]; Volkswagen FoundationVolkswagen [86042]; Telethon ItalyFondazione Telethon [GTB12001], This work was part of the CRANIRARE-2 Network funded by the German Federal Ministry of Education and Research (BMBF) (01GM1211A to B. W., 01GM1211B to D. W.), the TUBITAK (112S398 to H. K.) and ERARE-ANR CraniRare to S. L. This work was also funded by a grant (MRNET) from the German Federal Ministry of Education and Research (01GS08167 to D. W.), by DFG grants (BO 1955/2-3 and WU 314/6-2 to S. B. and D. W.) and by the Volkswagen Foundation (ref 86042 to A. W.). The biobank "Cell lines and DNA bank of Rett syndrome, X linked Mental Retardation and other genetic diseases", member of the Telethon Network of Genetic Biobanks (project no. GTB12001), funded by Telethon Italy, provided us with specimens.

Published
2017

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