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

Mol Psychiatry. 2018 Apr;23(4):973-984. doi: 10.1038/mp.2017.60.

R Harripaul ¹ ², N Vasli ¹, A Mikhailov ¹, M A Rafiq ¹ ³, K Mittal ¹, C Windpassinger ⁴, T I Sheikh ¹ ², A Noor ⁵ ⁶, H Mahmood ¹, S Downey ¹ ⁷, M Johnson ¹ ⁷, K Vleuten ¹ ⁷, L Bell ¹ ⁷, M Ilyas ⁸, F S Khan ⁹, V Khan ⁹, M Moradi ¹⁰, M Ayaz ¹¹, F Naeem ¹¹ ¹², A Heidari ¹ ¹³, I Ahmed ¹⁴, S Ghadami ¹⁵, Z Agha ³, S Zeinali ¹⁵, R Qamar ³ ¹⁶, H Mozhdehipanah ¹⁷, P John ¹⁴, A Mir ⁸, M Ansar ⁹, L French ¹⁸, M Ayub ¹¹ ¹², J B Vincent ¹ ² ¹⁹

Affiliations

1 Molecular Neuropsychiatry & Development (MiND) Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
2 Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
3 Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.
4 Institute of Human Genetics, Medical University of Graz, Graz, Austria.
5 Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada.
6 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
7 Fleming College, Peterborough, ON, Canada.
8 Human Molecular Genetics Lab, Department of Bioinformatics and Biotechnology, FBAS, International Islamic University, Islamabad, Pakistan.
9 Department of Biochemistry, Quaid-i-Azam University, Islamabad, Pakistan.
10 Qazvin University of Medical Science, Qazvin, Iran.
11 Lahore Institute of Research & Development, Lahore, Pakistan.
12 Department of Psychiatry, Queen's University, Kingston, ON, Canada.
13 Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada.
14 Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad, Pakistan.
15 Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran.
16 Department of Biochemistry, Al-Nafees Medical College, Isra University, Islamabad, Pakistan.
17 Department of Neurology, Qazvin University of Medical Sciences, Qazvin, Iran.
18 Computational Neurobiology Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
19 Department of Psychiatry, University of Toronto, Toronto, ON, Canada.

PMID: 28397838 DOI: 10.1038/mp.2017.60

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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