Seven Genes for X-Linked Intellectual Disability – (Correction)

Genetic analysis discovers new mutations on the X chromosome.

X-linked intellectual disability is a disorder that predominantly affects men and can have highly variable clinical manifestations. Scientists at the Max Planck Institute for Molecular Genetics in Berlin have found seven new genes that can cause this genetic disease: Mutations of these genes on the X chromosome lead to various forms of intellectual disability. In their work, the researchers used a method of genetic analysis that significantly simplifies the search for rare genetic defects.

X-linked intellectual disability is caused by defective genes on the X chromosome. As males only have one X chromosome and the disease is passed on in a recessive manner, the disorder mainly occurs in boys. Women are affected only if both their X chromosomes carry the defective genes. Women with one healthy and one mutated X chromosome are usually healthy but have a 50% chance of passing the mutated X chromosome on to their offspring.

X-linked intellectual disability is caused by defective genes on the X chromosome. This image is for illustrative purposes only and is in the public domain.
X-linked intellectual disability is caused by defective genes on the X chromosome. This image is for illustrative purposes only and is in the public domain.

Because of the high variability of the clinical picture, the search for the responsible genetic defect was, until a few years ago, very tedious. Some families have been waiting for over 15 years for the cause of their relative’s disorder to be clarified. An international research team headed by Max Planck researcher Vera Kalscheuer has now analysed 405 families, in which cases of X-linked intellectual disability occur. The researchers have discovered changes in a number of genes that were already known to be related to the disorder. In addition, they discovered that X-linked intellectual disability can also be caused by mutations in seven other genes that, until now, were not associated with the disorder.

For some years now, scientists have been aided in their research of genetic diseases by high-throughput sequencing. This technology allows to sequence a large number of DNA segments simultaneously and to more easily identify genetic defects. Using this method, the scientists investigated all DNA regions of the X chromosome containing protein-relevant information. “In addition to known disease-related genes, we have discovered seven novel genes as the cause of X-linked intellectual disability and analysed what signaling pathways in the cells each protein is involved in,” says Kalscheuer. According to the researchers, the clinical presentation and severity of the disorder depend on the responsible gene and the nature of the mutation. For example, if the mutation is located in a region that is important for brain development and protein function, the result is likely to be a more severe disease progression.

With the help of systematic re-sequencing of all X-linked genes, the responsible genetic defect can be identified in around 60 percent of families with X-linked intellectual disability. This requires that a condition known as fragile-X syndrome, caused by an expansion of a trinucleotide repeat, has been ruled out. However, this cannot be done with the method used here.

According to the scientists, the proteins associated with the newly discovered genes may also be involved in epilepsy, autism and schizophrenia. In future, the researchers aim to investigate the functions of the responsible proteins more closely in order to improve our understanding of what causes these and similar disorders.

About this genetics research

Contact: Dr. Vera Kalscheuer – Max Planck Institute
Source: Max Planck Institute press release
Image Source: The image is in the public domain
Original Research: (Correction to title) Full open access research for “X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes” by H Hu, S A Haas, J Chelly, H Van Esch, M Raynaud, A P M de Brouwer, S Weinert, G Froyen, S G M Frints, F Laumonnier, T Zemojtel, M I Love, H Richard, A-K Emde, M Bienek, C Jensen, M Hambrock, U Fischer, C Langnick, M Feldkamp, W Wissink-Lindhout, N Lebrun, L Castelnau, J Rucci, R Montjean, O Dorseuil, P Billuart, T Stuhlmann, M Shaw, M A Corbett, A Gardner, S Willis-Owen, C Tan, K L Friend, S Belet, K E P van Roozendaal, M Jimenez-Pocquet, M-P Moizard, N Ronce, R Sun, S O’Keeffe, R Chenna, A van Bömmel, J Göke, A Hackett, M Field, L Christie, J Boyle, E Haan, J Nelson, G Turner, G Baynam, G Gillessen-Kaesbach, U Müller, D Steinberger, B Budny, M Badura-Stronka, A Latos-Bieleńska, L B Ousager, P Wieacker, G Rodríguez Criado, M-L Bondeson, G Annerén, A Dufke, M Cohen, L Van Maldergem, C Vincent-Delorme, B Echenne, B Simon-Bouy, T Kleefstra, M Willemsen, J-P Fryns, K Devriendt, R Ullmann, M Vingron, K Wrogemann, T F Wienker, A Tzschach, H van Bokhoven, J Gecz, T J Jentsch, W Chen, H-H Ropers and V M Kalscheuer in Molecular Psychiatry. Published online February 3 2015 doi:10.1038/mp.2014.193

Open Access Neuroscience Abstract

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

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.

 (Correction to title) “X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes” by H Hu, S A Haas, J Chelly, H Van Esch, M Raynaud, A P M de Brouwer, S Weinert, G Froyen, S G M Frints, F Laumonnier, T Zemojtel, M I Love, H Richard, A-K Emde, M Bienek, C Jensen, M Hambrock, U Fischer, C Langnick, M Feldkamp, W Wissink-Lindhout, N Lebrun, L Castelnau, J Rucci, R Montjean, O Dorseuil, P Billuart, T Stuhlmann, M Shaw, M A Corbett, A Gardner, S Willis-Owen, C Tan, K L Friend, S Belet, K E P van Roozendaal, M Jimenez-Pocquet, M-P Moizard, N Ronce, R Sun, S O’Keeffe, R Chenna, A van Bömmel, J Göke, A Hackett, M Field, L Christie, J Boyle, E Haan, J Nelson, G Turner, G Baynam, G Gillessen-Kaesbach, U Müller, D Steinberger, B Budny, M Badura-Stronka, A Latos-Bieleńska, L B Ousager, P Wieacker, G Rodríguez Criado, M-L Bondeson, G Annerén, A Dufke, M Cohen, L Van Maldergem, C Vincent-Delorme, B Echenne, B Simon-Bouy, T Kleefstra, M Willemsen, J-P Fryns, K Devriendt, R Ullmann, M Vingron, K Wrogemann, T F Wienker, A Tzschach, H van Bokhoven, J Gecz, T J Jentsch, W Chen, H-H Ropers and V M Kalscheuer in Molecular Psychiatry. doi:10.1038/mp.2014.193

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