title: Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Holly A F
authors.initials: HAF
authors.lastname: Stessman
authors.affiliation: 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.
authors.forename: Marjolein H
authors.initials: MH
authors.lastname: Willemsen
authors.affiliation: 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.
authors.forename: Michaela
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authors.lastname: Fenckova
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Osnat
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authors.lastname: Penn
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiong
authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
authors.forename: Tianyun
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authors.lastname: Wang
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Kendra
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authors.lastname: Hoekzema
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Laura
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authors.lastname: Vives
authors.affiliation: Department of Clinical Genetics, Aarhus University Hospital, Skejby, 8000 Aarhus, Denmark.
authors.forename: Ida
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authors.lastname: Vogel
authors.affiliation: 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.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Ineke
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authors.lastname: van der Burgt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Charlotte W
authors.initials: CW
authors.lastname: Ockeloen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Janneke H
authors.initials: JH
authors.lastname: Schuurs-Hoeijmakers
authors.affiliation: Department of Genetics, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
authors.forename: Jolien S
authors.initials: JS
authors.lastname: Klein Wassink-Ruiter
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
authors.forename: Connie
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authors.lastname: Stumpel
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
authors.forename: Servi J C
authors.initials: SJC
authors.lastname: Stevens
authors.affiliation: Department of Neurologie, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
authors.forename: Hans S
authors.initials: HS
authors.lastname: Vles
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Marcelis
authors.affiliation: 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.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: 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.
authors.forename: Vincent
authors.initials: V
authors.lastname: Cantagrel
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.affiliation: 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.
authors.forename: Michael
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authors.lastname: Nicouleau
authors.affiliation: 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.
authors.forename: Stanislas
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authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Raphael A
authors.initials: RA
authors.lastname: Bernier
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98105, USA.
authors.forename: Jennifer
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authors.lastname: Gerdts
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98105, USA.
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authors.initials: BP
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authors.affiliation: Pediatrics & Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
authors.forename: Corrado
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authors.affiliation: Pediatrics & Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
authors.forename: Antonino
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authors.lastname: Alberti
authors.affiliation: Laboratory of Medical Genetics, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
authors.forename: Lucia
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authors.lastname: Grillo
authors.affiliation: Neuromuscular Diseases Unit, Istituto di Ricovero e Cura a Carattere Scientifico Associazione Oasi Maria Santissima, 94018 Troina, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Scuderi
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
authors.forename: Magnus
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authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 171 77 Solna, Sweden.
authors.forename: Malin
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authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
authors.forename: Hui
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authors.affiliation: The State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan 410078, China.
authors.forename: Kun
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authors.affiliation: 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.
authors.forename: Amélie
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authors.affiliation: Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
authors.forename: Bénédicte
authors.initials: B
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authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Genevieve
authors.affiliation: Centre de Génétique Chromosomique, Hôpital Saint Vincent de Paul, Groupement des Hôpitaux de l'Institut Catholique de Lille, 59000 Lille, France.
authors.forename: Bruno
authors.initials: B
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authors.affiliation: Équipe EA4271-GAD, Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Est, Fédération Hospitalo-Universitaire TRANSLAD, 21079 Dijon, France.
authors.forename: Daphne
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authors.affiliation: Service de Génétique Clinique, Hôpital Robert Debré, 75019 Paris, France.
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authors.affiliation: Équipe EA4271-GAD, Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Est, Fédération Hospitalo-Universitaire TRANSLAD, 21079 Dijon, France.
authors.forename: Julien
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authors.affiliation: Robinson Research Institute, University of Adelaide and Women's and Children's Hospital, North Adelaide SA 5006, Australia.
authors.forename: Jozef
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authors.affiliation: Robinson Research Institute, University of Adelaide and Women's and Children's Hospital, North Adelaide SA 5006, Australia.
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authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
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authors.affiliation: 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.
authors.forename: Boris
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authors.affiliation: 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.
authors.forename: Annette
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authors.affiliation: 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.
authors.forename: Evan E
authors.initials: EE
authors.lastname: Eichler
authors.affiliation: 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.
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mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D015536:Down-Regulation; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D007805:Language Development Disorders / Q000175:diagnosis / Q000235:genetics; D016014:Linear Models; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D019895:Transposases / Q000235:genetics*; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins
chemical_list: D029721:Drosophila Proteins; D014157:Transcription Factors; D019895:Transposases; C541037:POGZ protein, human; D004268:DNA-Binding Proteins; D018797:Cell Cycle Proteins; C535217:ROW protein, Drosophila