Helmholtz Gemeinschaft


X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes

[img] PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader

Official URL:https://doi.org/10.1038/mp.2014.193
PubMed:View item in PubMed
Creators Name:Hu, H. and Haas, S.A. and Chelly, J. and Van Esch, H. and Raynaud, M. and de Brouwer, A.P.M. and Weinert, S. and Froyen, G. and Frints, S.G.M. and Laumonnier, F. and Zemojtel, T. and Love, M.I. and Richard, H. and Emde, A.K. and Bienek, M. and Jensen, C. and Hambrock, M. and Fischer, U. and Langnick, C. and Feldkamp, M. and Wissink-Lindhout, W. and Lebrun, N. and Castelnau, L. and Rucci, J. and Montjean, R. and Dorseuil, O. and Billuart, P. and Stuhlmann, T. and Shaw, M. and Corbett, M.A. and Gardner, A. and Willis-Owen, S. and Tan, C. and Friend, K.L. and Belet, S. and van Roozendaal, K.E.P. and Jimenez-Pocquet, M. and Moizard, M.P. and Ronce, N. and Sun, R. and O'Keeffe, S. and Chenna, R. and van Boemmel, A. and Goeke, J. and Hackett, A. and Field, M. and Christie, L. and Boyle, J. and Haan, E. and Nelson, J. and Turner, G. and Baynam, G. and Gillessen-Kaesbach, G. and Mueller, U. and Steinberger, D. and Budny, B. and Badura-Stronka, M. and Latos-Bielenika, A. and Ousager, L.B. and Wieacker, P. and Rodriguez Criado, G. and Bondeson, M.L. and Anneren, G. and Dufke, A. and Cohen, M. and Van Maldergem, L. and Vincent-Delorme, C. and Echenne, B. and Simon-Bouy, B. and Kleefstra, T. and Willemsen, M. and Fryns, J.P. and Devriendt, K. and Ullmann, R. and Vingron, M. and Wrogemann, K. and Wienker, T.F. and Tzschach, A. and van Bokhoven, H. and Gecz, J. and Jentsch, T.J. and Chen, W. and Ropers, H.H. and Kalscheuer, V.M.
Journal Title:Molecular Psychiatry
Journal Abbreviation:Mol Psychiatr
Page Range:133-148
Date:January 2016
Keywords:Chloride Channels, Cohort Studies, Cultured Cells, Cyclin-Dependent Kinases, Genetic Variation, High-Throughput Nucleotide Sequencing, Histone Acetyltransferases, Intracellular Signaling Peptides and Proteins, Messenger RNA, Microfilament Proteins, Neurons, Nuclear Proteins, Signal Transducing Adaptor Proteins, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Ubiquitin-Protein Ligases, X-Linked Mental Retardation, Animals, Mice
Abstract:X-linked intellectual disability (XLID) is a clinically and genetically heterogeneous disorder. During the past two decades in excess of 100 X-chromosome ID genes have been identified. Yet, a large number of families mapping to the X-chromosome remained unresolved suggesting that more XLID genes or loci are yet to be identified. Here, we have investigated 405 unresolved families with XLID. We employed massively parallel sequencing of all X-chromosome exons in the index males. The majority of these males were previously tested negative for copy number variations and for mutations in a subset of known XLID genes by Sanger sequencing. In total, 745 X-chromosomal genes were screened. After stringent filtering, a total of 1297 non-recurrent exonic variants remained for prioritization. Co-segregation analysis of potential clinically relevant changes revealed that 80 families (20%) carried pathogenic variants in established XLID genes. In 19 families, we detected likely causative protein truncating and missense variants in 7 novel and validated XLID genes (CLCN4, CNKSR2, FRMPD4, KLHL15, LAS1L, RLIM and USP27X) and potentially deleterious variants in 2 novel candidate XLID genes (CDK16 and TAF1). We show that the CLCN4 and CNKSR2 variants impair protein functions as indicated by electrophysiological studies and altered differentiation of cultured primary neurons from Clcn4(-/-) mice or after mRNA knock-down. The newly identified and candidate XLID proteins belong to pathways and networks with established roles in cognitive function and intellectual disability in particular. We suggest that systematic sequencing of all X-chromosomal genes in a cohort of patients with genetic evidence for X-chromosome locus involvement may resolve up to 58% of Fragile X-negative cases.
Publisher:Nature Publishing Group (U.K.)
Item Type:Article

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library