Genetics of intellectual disability in consanguineous families


Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

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We are grateful to all patients and families for their participation in this study, S. Banihashemi and Kh. Jalalvand for technical support and Gabriele Eder for assisting us with the preparation of the manuscript. We would also like to thank the NHLBI GO Exome Sequencing Project and its ongoing studies, as well as the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at This research was supported by the European Union through FP7 project GENCODYS, grant no 241995 (organizer: Hans van Bokhoven), the Max Planck Innovation Funds and the Ministry of Health and Medical Education, Islamic Republic Iran. Additional support was received from the Iranian National Science Foundation (grant no.s 92038458 and 92035782), the Iranian National Elite Foundation and the Iranian Science Elite Federation.

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Correspondence to Hans-Hilger Ropers or Hossein Najmabadi.

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Hu, H., Kahrizi, K., Musante, L. et al. Genetics of intellectual disability in consanguineous families. Mol Psychiatry 24, 1027–1039 (2019).

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