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Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability

Abstract

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.

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Figure 1: Identification of IQSEC2 mutations.
Figure 2: IQSEC2 structure and mutations.

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Acknowledgements

We would like to express our gratitude to the participating individuals and families and to N. Briggs for assistance with statistical analysis. The work has been supported by the Australian National Health and Medical Research Council to J.G., the SMILE Foundation, the Women's and Children's Hospital Foundation, D. Harwood, US National Institutes of Health (HD26202) to C.E.S., the South Carolina Department of Disabilities and Special Needs (SCDDSN), the Medical Research Council (S.R. and R.J.H.), Action Medical Research and the Wellcome Trust for support under grant reference 077012/Z/05/Z.

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Contributions

C.S., M.S., F.A., A.G. and J.B. assembled the extended families and confirmed, tracked and analyzed the changes. A.P., H.P. and M.S. performed additional subject and control screening. P.S.T., A.F. and M.R.S. supervised the X-chromosome sequencing, collation and analysis of the sequencing data. A.H., M.F., R.E.S., G.T., C.E.S. and F.L.R. contributed families and clinical data on affected individuals. C.S., S.L.R., J.A.M., R.S.W., R.J.H. and S.R. performed functional assays. C.S. and J.G. conceived and designed the study and wrote the first draft of the manuscript. J.G. directed the study. All authors contributed to discussion of the results and manuscript preparation.

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Correspondence to Cheryl Shoubridge or Jozef Gécz.

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The authors declare no competing financial interests.

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Supplementary Methods, Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1 and 2 (PDF 958 kb)

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Shoubridge, C., Tarpey, P., Abidi, F. et al. Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability. Nat Genet 42, 486–488 (2010). https://doi.org/10.1038/ng.588

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