Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features

Allen N. Lamb, Jill A. Rosenfeld, Nicholas J. Neill, Michael E. Talkowski, Ian Blumenthal, Santhosh Girirajan, Debra Keelean-Fuller, Zheng Fan, Jill Pouncey, Cathy Stevens, Loren Mackay-Loder, Deborah Terespolsky, Patricia I. Bader, Kenneth Rosenbaum, Stephanie E. Vallee, John B. Moeschler, Roger Ladda, Susan Sell, Judith Martin, Shawnia RyanMarilyn C. Jones, Rocio Moran, Amy Shealy, Suneeta Madan-Khetarpal, Juliann Mcconnell, Urvashi Surti, Andrée Delahaye, Bénédicte Heron-Longe, Eva Pipiras, Brigitte Benzacken, Sandrine Passemard, Alain Verloes, Bertrand Isidor, Cedric Le Caignec, Gwen M. Glew, Kent E. Opheim, Maria Descartes, Evan E. Eichler, Cynthia C. Morton, James F. Gusella, Roger A. Schultz, Blake C. Ballif, Lisa G. Shaffer

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.

Original languageEnglish (US)
Pages (from-to)728-740
Number of pages13
JournalHuman mutation
Volume33
Issue number4
DOIs
StatePublished - Apr 2012

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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    Lamb, A. N., Rosenfeld, J. A., Neill, N. J., Talkowski, M. E., Blumenthal, I., Girirajan, S., Keelean-Fuller, D., Fan, Z., Pouncey, J., Stevens, C., Mackay-Loder, L., Terespolsky, D., Bader, P. I., Rosenbaum, K., Vallee, S. E., Moeschler, J. B., Ladda, R., Sell, S., Martin, J., ... Shaffer, L. G. (2012). Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features. Human mutation, 33(4), 728-740. https://doi.org/10.1002/humu.22037