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Article Dans Une Revue American Journal of Human Genetics Année : 2016

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

1 GS - Department of Genome Sciences [Seattle]
2 849 Department of Human Genetics
3 State Key Laboratory of Medical Genetics of China
4 Department of Clinical Genetics
5 UMCG - University Medical Center Groningen [Groningen]
6 Department of Clinical Genetics
7 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
8 Hôpital Necker - Enfants Malades [AP-HP]
9 UW psychiatry - Department of Psychiatry and Behavioral Sciences!
10 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
11 IG - Institut de Génomique d'Evry
12 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
13 Department of Microbiology
14 Department of Molecular Medicine and Surgery and Center for Molecular Medicine
15 Karolinska Institutet [Stockholm]
16 CUHK - The Chinese University of Hong Kong [Hong Kong]
17 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
18 DGA.MI - DGA Maîtrise de l'information
19 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
20 Centre de Génétique Chromosomique
21 GAD - Génétique des Anomalies du Développement
22 SnT - Interdisciplinary Centre for Security, Reliability and Trust [Luxembourg]
23 AMAPP - Activité Motrice et Adaptation PsychoPhysiologique
24 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
25 University of Adelaide
26 UND - University of Notre Dame [Indiana]
27 Department of Human Genetics
28 CHU Pitié-Salpêtrière [AP-HP]
29 UPMC - Université Pierre et Marie Curie - Paris 6
30 IGBMC - Institut de génétique et biologie moléculaire et cellulaire
Ida Vogel
Hui Guo
  • Fonction : Auteur
Jozef Gecz


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.

Dates et versions

hal-01405534 , version 1 (30-11-2016)



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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