Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders

Holly A.F. Stessman, Marjolein H. Willemsen, Michaela Fenckova, Osnat Penn, Alexander Hoischen, Bo Xiong, Tianyun Wang, Kendra Hoekzema, Laura Vives, Ida Vogel, Han G. Brunner, Ineke Van Der Burgt, Charlotte W. Ockeloen, Janneke H. Schuurs-Hoeijmakers, Jolien S. Klein Wassink-Ruiter, Connie Stumpel, Servi J.C. Stevens, Hans S. Vles, Carlo M. Marcelis, Hans Van BokhovenVincent Cantagrel, Laurence Colleaux, Michael Nicouleau, Stanislas Lyonnet, Raphael A. Bernier, Jennifer Gerdts, Bradley P. Coe, Corrado Romano, Antonino Alberti, Lucia Grillo, Carmela Scuderi, Magnus Nordenskjöld, Malin Kvarnung, Hui Guo, Kun Xia, Amélie Piton, Bénédicte Gerard, David Genevieve, Bruno Delobel, Daphne Lehalle, Laurence Perrin, Fabienne Prieur, Julien Thevenon, Jozef Gecz, Marie Shaw, Rolph Pfundt, Boris Keren, Aurelia Jacquette, Annette Schenck, Evan E. Eichler, Tjitske Kleefstra

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Abstract

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID. The rarity of disruptive mutations among unaffected individuals (2/49,401) highlights the significance (p = 4.19 × 10-13; odds ratio = 35.8) and penetrance (65.9%) of this genetic subtype with respect to ASD and ID. By studying the entire cohort, we defined common phenotypic features of POGZ individuals, including variable levels of developmental delay (DD) and more severe speech and language delay in comparison to the severity of motor delay and coordination issues. We also identified significant associations with vision problems, microcephaly, hyperactivity, a tendency to obesity, and feeding difficulties. Some features might be explained by the high expression of POGZ, particularly in the cerebellum and pituitary, early in fetal brain development. We conducted parallel studies in Drosophila by inducing conditional knockdown of the POGZ ortholog row, further confirming that dosage of POGZ, specifically in neurons, is essential for normal learning in a habituation paradigm. Combined, the data underscore the pathogenicity of loss-of-function mutations in POGZ and define a POGZ-related phenotype enriched in specific features.

Original languageEnglish (US)
Pages (from-to)541-552
Number of pages12
JournalAmerican journal of human genetics
Volume98
Issue number3
DOIs
StatePublished - Mar 3 2016
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Stessman, H. A. F., Willemsen, M. H., Fenckova, M., Penn, O., Hoischen, A., Xiong, B., Wang, T., Hoekzema, K., Vives, L., Vogel, I., Brunner, H. G., Van Der Burgt, I., Ockeloen, C. W., Schuurs-Hoeijmakers, J. H., Klein Wassink-Ruiter, J. S., Stumpel, C., Stevens, S. J. C., Vles, H. S., Marcelis, C. M., ... Kleefstra, T. (2016). Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders. American journal of human genetics, 98(3), 541-552. https://doi.org/10.1016/j.ajhg.2016.02.004