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Am J Hum Genet. 2016 Mar 3;98(3):541-552. doi: 10.1016/j.ajhg.2016.02.004.

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

Author information

1
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
2
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: marjolein.willemsen@radboudumc.nl.
3
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
4
The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
5
Department of Clinical Genetics, Aarhus University Hospital, Skejby, 8000 Aarhus, Denmark.
6
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
7
Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
8
Department of Genetics, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
9
Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
10
Department of Neurologie, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
11
INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France.
12
INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, 75015 Paris, France; Paris Descartes University - Sorbonne Paris Cité, Imagine Institute, 75015 Paris, France; Departments of Genetics, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris, 75015 Paris, France.
13
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98105, USA.
14
Pediatrics & Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
15
Laboratory of Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
16
Neuromuscular Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
17
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
18
Department of Translational Medicine and Neurogenetics, Institut Génétique Biologie Moléculaire Cellulaire, 67400 Illkirch, France; Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
19
Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
20
Département de Génétique Médicale, Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Languedoc Roussillon, Hôpital Arnaud de Villeneuve, 34090 Montpellier, France.
21
Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l'Institut Catholique de Lille, 59000 Lille, France.
22
Équipe EA4271-GAD, Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Est, Fédération Hospitalo-Universitaire TRANSLAD, 21079 Dijon, France.
23
Service de Génétique Clinique, Hôpital Robert Debré, 75019 Paris, France.
24
Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de Saint-Étienne, 42100 Saint-Étienne, France.
25
Robinson Research Institute, University of Adelaide and Women's and Children's Hospital, North Adelaide SA 5006, Australia.
26
Département de Génétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France; INSERM UM75 and U1127, CNRS UMR7225, Université Pierre et Marie Curie (Paris 6) and Institut du Cerveau et de la Moelle épinière, 75013 Paris, France.
27
Département de Génétique, Hôpital de la Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France.
28
Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA; Howard Hughes Medical Institute, Seattle, WA 98195, USA. Electronic address: eee@gs.washington.edu.

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.

PMID:
26942287
PMCID:
PMC4890241
DOI:
10.1016/j.ajhg.2016.02.004
[Indexed for MEDLINE]
Free PMC Article

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