Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Riazuddin, S., Hussain, M., Razzaq, A., Iqbal, Z., Shahzad, M., Polla, D. L., Song, Y., van Beusekom, E., Khan, A. A., Tomas-Roca, L., Rashid, M., Zahoor, M. Y., Wissink-Lindhout, W. M., Basra, M. A. R., Ansar, M., Agha, Z., van Heeswijk, K., Rasheed, F., Van de Vorst, M., Veltman, J. A., Gilissen, C., Akram, J., Kleefstra, T., Assir, M. Z., Grozeva, D., Carss, K., Raymond, F. L., O'Connor, T. D., Riazuddin, S. A., Khan, S. N., Ahmed, Z. M., de Brouwer, A. P. M., van Bokhoven, H. and Riazuddin, S. 2017. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Molecular Psychiatry 22 (11) , pp. 1604-1614. 10.1038/mp.2016.109

Full text not available from this repository.


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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Springer Nature
ISSN: 1359-4184
Date of Acceptance: 1 June 2016
Last Modified: 03 Sep 2019 09:16

Citation Data

Cited 70 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item