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

Holly a.F. Stessman 1 Marjolein h. Willemsen 2, * Michael Fenckova 2 Osnat Penn 1 Alexander Hoischen 2 Bo Xiong 1 Tianyun Wang 3 Kendra Hoekzema 1 Laura Vives 1 Ida Vogel 4 Han g. Brunner 2 Ineke Van der burgt 2 Charlotte W. Ockeloen 2 Janneke H. Schuurs-Hoeijmakers 2 Jolien s. Klein wassink-Ruiter 5 Connie Stumpel 5 Servi j.C. Stevens 6 Hans Vles 6 Carlo M. Marcelis 2 Hans Van bokhoven 2 Vincent Cantagrel 7 Laurence Colleaux 7 Michael Nicouleau 7 Stanislas Lyonnet 8, 7 Raphael a. Bernier 9 Jennifer Gerdts 9 Bradley p. Coe 1 Corrado Romano 10 Antonino Alberti 11 Lucia Grillo 12 Carmela Scuderi 13 Magnus Nordenskjöld 14 Malin Kvarnung 15 Hui Guo Kun Xia 16 Amélie Piton 17 Bénédicte Gerard 18 David Genevieve 19 Bruno Delobel 20 Daphne Lehalle 21 Laurence Perrin 22 Fabienne Prieur 23 Julien Thevenon 24, 21 Jozef Gecz 25 Marie Shaw 26 Rolph Pfundt 27 Boris Keren 28, 29 Aurelia Jacquette 28 Annette Schenck 30 Evan e. Eichler 1, * Tjitske Kleefstra 2 
* Auteur correspondant
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 x 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.
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Soumis le : mercredi 30 novembre 2016 - 10:28:59
Dernière modification le : jeudi 20 octobre 2022 - 15:10:07

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Holly a.F. Stessman, Marjolein h. Willemsen, Michael Fenckova, Osnat Penn, Alexander Hoischen, et al.. Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders. American Journal of Human Genetics, 2016, 98 (3), pp.541 - 552. ⟨10.1016/j.ajhg.2016.02.004⟩. ⟨hal-01405534⟩



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