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OMICS. 2017 May;21(5):295-303. doi: 10.1089/omi.2017.0009.

Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability.

Author information

1 Institute of Bioinformatics , International Technology Park, Bangalore, India .
2 Centre for Bioinformatics, Pondicherry University , Puducherry, India .
3 Molecular Biology Department, Genentech, Inc. , South San Francisco, California.
4 Department of Child and Adolescent Psychiatry, NIMHANS , Bangalore, India .
5 Department of Bioinformatics and Computational Biology, Genentech, Inc. , South San Francisco, California.
6 Department of Structural Biology, Genentech, Inc. , South San Francisco, California.
7 MedGenome , Bangalore, India .
8 Centre for Human Genetics , Biotech Park, Bangalore, India .
9 YU-IOB Center for Systems Biology and Molecular Medicine, Yenepoya University , Mangalore, India .
10 NIMHANS-IOB Proteomics and Bioinformatics Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences , Bangalore, India .
11 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine , Baltimore, Maryland.
12 Department of Biological Chemistry, Johns Hopkins University School of Medicine , Baltimore, Maryland.
13 Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland.


Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.


diagnostic medicine; genotype–phenotype association; mental retardation; neurodevelopmental disorders; next-generation sequencing

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