English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

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

Hu, H., Haas, S. A., Chelly, J., Van Esch, H., Raynaud, M., de Brouwer, A. P. M., et al. (2016). X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Molecular Psychiatry, 21(1), 133-148. doi:10.1038/mp.2014.193.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-7A74-C Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6111-5
Genre: Journal Article

Files

show Files
hide Files
:
Hu.pdf (Publisher version), 3MB
Name:
Hu.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© 2015 Macmillan Publishers Limited

Locators

show

Creators

show
hide
 Creators:
Hu, H.1, Author              
Haas, S. A.2, Author              
Chelly, J., Author
Van Esch, H., Author
Raynaud, M., Author
de Brouwer, A. P. M., Author
Weinert, S., Author
Froyen, G., Author
Frints, S. G. M., Author
Laumonnier, F., Author
Zemojtel, T.3, Author              
Love, M. I.4, Author              
Richard, H., Author
Emde, A.-K.2, Author              
Bienek, M.1, Author              
Jensen, C., Author
Hambrock, M.5, Author              
Fischer, U., Author
Langnick, C., Author
Feldkamp, M., Author
Wissink-Lindhout, W., AuthorLebrun, N., AuthorCastelnau, L., AuthorRucci, J., AuthorMontjean, R., AuthorDorseuil, O., AuthorBilluart, P., AuthorStuhlmann, T., AuthorShaw, M., AuthorCorbett, M. A., AuthorGardner, A., AuthorWillis-Owen, S., AuthorTan, C., AuthorFriend, K. L., AuthorBelet, S., Authorvan Roozendaal, K. E. P., AuthorJimenez-Pocquet, M., AuthorMoizard, M.-P., AuthorRonce, N., AuthorSun, R.2, Author              O'Keeffe, S., AuthorChenna, R., Authorvan Bömmel, A.3, Author              Göke, J.3, Author              Hackett, A., AuthorField, M., AuthorChristie, L., AuthorBoyle, J., AuthorHaan, E., AuthorNelson, J., AuthorTurner, G., AuthorBaynam, G., AuthorGillessen-Kaesbach, G., AuthorMüller, U., AuthorSteinberger, D., AuthorBudny, B., AuthorBadura-Stronka, M., AuthorLatos-Bieleńska, A., AuthorOusager, L. B., AuthorWieacker, P., AuthorRodríguez Criado, G., AuthorBondeson, M.-L., AuthorAnnerén, G., AuthorDufke, A., AuthorCohen, M., AuthorVan Maldergem, L., AuthorVincent-Delorme, C., AuthorEchenne, B., AuthorSimon-Bouy, B., AuthorKleefstra, T., AuthorWillemsen, M., AuthorFryns, J.-P., AuthorDevriendt, K., AuthorUllmann, R.6, Author              Vingron, M.7, Author              Wrogemann, K., AuthorWienker, T. F.8, Author              Tzschach, A., Authorvan Bokhoven, H., AuthorGecz, J., AuthorJentsch, T. J., AuthorChen, W.1, Author              Ropers, H.-H.1, Author              Kalscheuer, V. M.5, 9, Author               more..
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479640              
3Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              
4IMPRS for Computational Biology and Scientific Computing - IMPRS-CBSC (Kirsten Kelleher), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479666              
5Chromosome Rearrangements and Disease (Vera Kalscheuer), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              
6Molecular Cytogenetics (Reinhard Ullmann), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479645              
7Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479639              
8Clinical Genetics (Thomas F. Wienker), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, 1479643              
9Chromosome Rearrangements and Disease (Vera Kalscheuer), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479642              

Content

show
hide
Free keywords: -
 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.

Details

show
hide
Language(s): eng - English
 Dates: 2015-02-032016-01
 Publication Status: Published in print
 Pages: 16
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1038/mp.2014.193
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: Molecular Psychiatry
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: Macmillan Publishers Limited
Pages: - Volume / Issue: 21 (1) Sequence Number: - Start / End Page: 133 - 148 Identifier: ISSN: 1359-4184
CoNE: https://pure.mpg.de/cone/journals/resource/954925619131