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Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.

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

Author information

1
Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
2
Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
3
University Paris Descartes, Paris, France.
4
Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Institut National de la Santé et de la Recherche Médicale Unité 1016, Institut Cochin, Paris, France.
5
Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium.
6
Inserm U930 'Imaging and Brain', Tours, France.
7
University François-Rabelais, Tours, France.
8
Centre Hospitalier Régional Universitaire, Service de Génétique, Tours, France.
9
Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.
10
Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
11
Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
12
Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.
13
Human Genome Laboratory, Department of Human Genetics, K.U. Leuven, Leuven, Belgium.
14
Department of Clinical Genetics, Maastricht University Medical Center, azM, Maastricht, The Netherlands.
15
School for Oncology and Developmental Biology, GROW, Maastricht University, Maastricht, The Netherlands.
16
School of Paediatrics and Reproductive Health, The University of Adelaide, Adelaide, SA, Australia.
17
Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia.
18
National Heart and Lung Institute, Imperial College London, London, UK.
19
SA Pathology, Women's and Children's Hospital, Adelaide, SA, Australia.
20
Genetics of Learning and Disability Service, Hunter Genetics, Waratah, NSW, Australia.
21
Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia.
22
School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
23
Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia.
24
Telethon Kids Institute, Perth, WA, Australia.
25
Institut für Humangenetik, Universität zu Lübeck, Lübeck, Germany.
26
Institut für Humangenetik, Justus-Liebig-Universität Giessen, Giessen, Germany.
27
bio.logis Center for Human Genetics, Frankfurt a. M., Germany.
28
Chair and Department of Endocrinology, Metabolism and Internal Diseases, Ponzan University of Medical Sciences, Poznan, Poland.
29
Chair and Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland.
30
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
31
Institut für Humangenetik, Universitätsklinikum Münster, Muenster, Germany.
32
Unidad de Genética Clínica, Hospital Virgen del Rocío, Sevilla, España.
33
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
34
Institut für Medizinische Genetik und Angewandte Genomik, Tübingen, Germany.
35
Kinderzentrum München, München, Germany.
36
Centre de Génétique Humaine, Université de Franche-Comté, Besançon, France.
37
Service de Génétique, Hôpital Jeanne de Flandre CHRU de Lilles, Lille, France.
38
Service de Neuro-Pédiatrie, CHU Montpellier, Montpellier, France.
39
Laboratoire SESEP, Centre hospitalier de Versailles, Le Chesnay, France.
40
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.

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.

PMID:
25644381
PMCID:
PMC5414091
DOI:
10.1038/mp.2014.193
[Indexed for MEDLINE]
Free PMC Article

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