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

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.

SUBMITTER: Hu H

PROVIDER: S-EPMC5414091 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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

Hu H H Haas S A SA Chelly J J Van Esch H H Raynaud M M de Brouwer A P M AP Weinert S S Froyen G G Frints S G M SG Laumonnier F F Zemojtel T T Love M I MI Richard H H Emde A-K AK Bienek M M Jensen C C Hambrock M M Fischer U U Langnick C C Feldkamp M M Wissink-Lindhout W W Lebrun N N Castelnau L L Rucci J J Montjean R R Dorseuil O O Billuart P P Stuhlmann T T Shaw M M Corbett M A MA Gardner A A Willis-Owen S S Tan C C Friend K L KL Belet S S van Roozendaal K E P KE Jimenez-Pocquet M M Moizard M-P MP Ronce N N Sun R R O'Keeffe S S Chenna R R van Bömmel A A Göke J J Hackett A A Field M M Christie L L Boyle J J Haan E E Nelson J J Turner G G Baynam G G Gillessen-Kaesbach G G Müller U U Steinberger D D Budny B B Badura-Stronka M M Latos-Bieleńska A A Ousager L B LB Wieacker P P Rodríguez Criado G G Bondeson M-L ML Annerén G G Dufke A A Cohen M M Van Maldergem L L Vincent-Delorme C C Echenne B B Simon-Bouy B B Kleefstra T T Willemsen M M Fryns J-P JP Devriendt K K Ullmann R R Vingron M M Wrogemann K K Wienker T F TF Tzschach A A van Bokhoven H H Gecz J J Jentsch T J TJ Chen W W Ropers H-H HH Kalscheuer V M VM

Molecular psychiatry 20150203 1

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 the ...[more]

PMID: 25644381

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Project description:BACKGROUND: X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. METHODS & OBJECTIVES: Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. RESULTS: We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G?>?C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. CONCLUSIONS: All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations and the challenges of interpreting the results. Further functional studies are required to confirm the cause of the syndromic phenotypes associated with ZMYM3 and SYP in this study.

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

Publications

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

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