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Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families

Abstract

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

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Acknowledgements

We thank the study participants and their families for their invaluable contributions to this study. We also thank Justin Foong and Andy Wang for their assistance in setting up the NGS analysis pipeline on the CAMH SCC. Computations were performed on the CAMH Specialized Computing Cluster. The SCC is funded by The Canada Foundation for Innovation and the Research Hospital Fund. We also acknowledge the assistance of Muhammad Aslam (LIRD), Tanveer Nasr (Mayo Hospital, Lahore and Chaudhry Hospital, Gujranwala, Pakistan), Muhammad Ilyas (International Islamic University, Islamabad, Pakistan), Reza Najafipour and Soraya Keshavarz (Qazvin University of Medical Science) and Ali Rashidi-Nezhad (Tehran University of Medical Sciences) for family recruitment and phenotyping. We also thank Drs Hans van Bokhoven and Arjen de Brower (Radboud University Medical Center, Nijmegen, The Netherlands), who provided microarray SNP data for families ZA5 and ZA17. RH was supported by a Peterborough K.M. Hunter Charitable Foundation Graduate Scholarship. This study was partially supported by a grant from the Canadian Institutes of Health Research to JBV (#MOP-102758), as well as support through private donations to the Centre for Addiction & Mental Health Foundation.

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Harripaul, R., Vasli, N., Mikhailov, A. et al. Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families. Mol Psychiatry 23, 973–984 (2018). https://doi.org/10.1038/mp.2017.60

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