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Mol Psychiatry. 2017 Nov;22(11):1604-1614. doi: 10.1038/mp.2016.109. Epub 2016 Jul 26.

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

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Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland, School of Medicine, Baltimore, MD, USA.
Center for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Pakistan Institute of Medical Sciences, Islamabad, Pakistan.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Allama Iqbal Medical College, University of Health Sciences, Lahore, Pakistan.
National Centre of Excellence in Molecular Biology, University of The Punjab, Lahore, Pakistan.
Center for Genetic Diseases, CAPES Foundation, Ministry of Education of Brazil, Brasília, Brazil.
Institute for Genome Sciences and Program in Personalized and Genomic Medicine, University of Maryland, School of Medicine, Baltimore, MD, USA.
Department of Biosciences, Faculty of Science, COMSATS Institute of Information Technology, Islamabad, Pakistan.
Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Department of Haematology, University of Cambridge, Cambridge, UK.
Department of Ophthalmology, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.


Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

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