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CCDC22: a novel candidate gene for syndromic X-linked intellectual disability

Molecular Psychiatry volume 17, pages 4–7 (2012)Cite this article

X-linked intellectual disability (XLID), defined as clinical ID combined with a pedigree consistent with X-linked inheritance, is a genetically heterogeneous condition that affects more than 10% of males with ID. Currently there are at least 92 genes known to cause XLID,1, 2, 3 yet a large proportion of XLID cases remain unexplained, as each of the XLID genes identified so far only accounts for a small fraction (<1%) of affected individuals. Given that about one third of mutations affect gene expression levels,4 we reasoned that transcriptome profiling of lymphoblast cell lines from XLID patients may highlight genes harboring disease-causing mutations and may be an efficient follow-up method for rare sequence variants of unknown functional significance.

We analyzed expression profiles of lymphoblast cell lines from 64 XLID patients, including 13 cases that were part of a recent X-chromosome exon re-sequencing study5 (Supplementary Methods, Supplementary Table 1). We found polyglutamine-binding protein 1 (PQBP1), a gene previously implicated in XLID,6, 7 to be significantly downregulated in two cases (Supplementary Table 2), and confirmed an exon 4 (AG)2 deletion as the cause of mRNA downregulation in both instances. PQBP1 mutations cause a sydromic form of XLID commonly referred to as Renpenning syndrome.8 The specific mutation we describe here has been previously shown to cause XLID,6 and has also been proven to decrease mRNA levels by nonsense-mediated mRNA decay,7 thus being likely to be detected by assessment of gene expression. The cases for which we identified PQBP1 mutations were not part of the cohort studied by Tarpey et al. (Supplementary Table 1).

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Author notes

  1. I Voineagu and L Huang: These authors contributed equally to this work

Authors and Affiliations

  1. Program in Neurogenetics and Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    I Voineagu, K Winden, M Lazaro & D Geschwind

  2. Department of Genetics Medicine, SA Pathology, Adelaide, SA, Australia

    L Huang, E Haan, L S Nguyen, K Friend & J Gecz

  3. Institute of Reproductive and Stem Cell Engineering, Central South University, Changsha, China

    L Huang

  4. South Australian Clinical Genetics Service, SA Pathology, Adelaide, SA, Australia

    E Haan

  5. Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, WA, Australia

    J Nelson

  6. Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia

    J McGaughran

  7. University of Queensland, Brisbane, QLD, Australia

    J McGaughran

  8. Department of Pediatrics, The University of Adelaide, Adelaide, SA, Australia

    L S Nguyen & J Gecz

  9. The GOLD Service, Hunter Genetics, Waratah, NSW, Australia

    A Hackett & M Field

  10. Women's and Children's Health Research Institute, North Adelaide, SA, Australia

    J Gecz

  11. School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide, SA, Australia

    J Gecz

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  1. I Voineagu
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Corresponding author

Correspondence to D Geschwind.

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Voineagu, I., Huang, L., Winden, K. et al. CCDC22: a novel candidate gene for syndromic X-linked intellectual disability. Mol Psychiatry 17, 4–7 (2012). https://doi.org/10.1038/mp.2011.95

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