2. Academic Validation
  3. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

  • Genet Med. 2020 Mar;22(3):538-546. doi: 10.1038/s41436-019-0693-9.
Ghayda M Mirzaa 1 2 3,  Jessica X Chong 4 5,  Amélie Piton 6 7,  Bernt Popp 8,  Kimberly Foss 9,  Hui Guo 10,  Ricardo Harripaul 11 12,  Kun Xia 10,  Joshua Scheck 9,  Kimberly A Aldinger 9,  Samin A Sajan 13,  Sha Tang 14,  Dominique Bonneau 15 16,  Anita Beck 4,  Janson White 17,  Sonal Mahida 18,  Jacqueline Harris 18,  Constance Smith-Hicks 18,  Juliane Hoyer 8,  Christiane Zweier 8,  André Reis 8,  Christian T Thiel 8,  Rami Abou Jamra 19,  Natasha Zeid 20,  Amy Yang 21,  Laura S Farach 22,  Laurence Walsh 23,  Katelyn Payne 23,  Luis Rohena 24 25,  Milen Velinov 26,  Alban Ziegler 15 27,  Elise Schaefer 28,  Vincent Gatinois 29 30 31,  David Geneviève 29 30 31,  Marleen E H Simon 32,  Jennefer Kohler 33,  Joshua Rotenberg 34,  Patricia Wheeler 35,  Austin Larson 36,  Michelle E Ernst 37,  Cigdem I Akman 37 38,  Rachel Westman 39,  Patricia Blanchet 30,  Lori-Anne Schillaci 40,  Catherine Vincent-Delorme 41,  Karen W Gripp 42,  Francesca Mattioli 43,  Gwenaël Le Guyader 44,  Bénédicte Gerard 6,  Michèle Mathieu-Dramard 45,  Gilles Morin 46,  Roksana Sasanfar 46,  Muhammad Ayub 47,  Nasim Vasli 48,  Sandra Yang 49,  Rick Person 49,  Kristin G Monaghan 49,  Deborah A Nickerson 17,  Ellen van Binsbergen 32,  Gregory M Enns 33 50,  Annika M Dries 33,  Leah J Rowe 36,  Anne C H Tsai 36,  Shayna Svihovec 36,  Jennifer Friedman 51 52,  Zehra Agha 53,  Raheel Qamar 53,  Lance H Rodan 54 55,  Julian Martinez-Agosto 56,  Charlotte W Ockeloen 57,  Marie Vincent 58,  William James Sunderland 59,  Jonathan A Bernstein 33 50,  Undiagnosed Diseases Network,,  Evan E Eichler 17 60,  John B Vincent 11 12,  University of Washington Center for Mendelian Genomics (UW-CMG),,  Michael J Bamshad 4 5
Affiliations

Affiliations

  • 1 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA. [email protected].
  • 2 Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA. [email protected].
  • 3 Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA. [email protected].
  • 4 Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
  • 5 Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA.
  • 6 Molecular Genetic Unit, Strasbourg University Hospital, Strasbourg, France.
  • 7 Institute of Genetics and Molecular and Cellular Biology, Université de Strasbourg, Illkirch, France.
  • 8 Institute of Human Genetics, University Hospital Elrangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
  • 9 Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
  • 10 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
  • 11 The Campbell Family Mental Health Research Institute, Centre for Addiction & Mental Health (CAMH), Toronto, ON, Canada.
  • 12 Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
  • 13 Department of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA.
  • 14 WuXi NextCODE, Cambridge, MA, USA.
  • 15 Département de Biochimie et de Génétique, CHU d'Angers, Angers, France.
  • 16 UMR INSERM 1083 CNRS 6015, Angers, France.
  • 17 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA.
  • 18 Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 19 Institute of Human Genetics, University Medical Center Leipzig, Leipzig, Germany.
  • 20 Yale New Haven Health, New Haven, CT, USA.
  • 21 Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR, USA.
  • 22 Department of Pediatrics, McGovern Medical School at the University of Texas Health Sciences Center, Houston, TX, USA.
  • 23 Indiana University Health at Riley Hospital for Children, Indianapolis, IN, USA.
  • 24 Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, San Antonio, TX, USA.
  • 25 Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
  • 26 New York State Institute for Basic Research in Developmental Disability, NY, Staten Island, USA.
  • 27 Service de Génétique Médicale, Centre hospitalier, Le Mans, France.
  • 28 Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Institut de Génétique Médicale d'Alsace, Strasbourg, France.
  • 29 Service de génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Strasbourg, France.
  • 30 Centre de Référence Maladies Rares Anomalies du Développement et Syndromes Malformatifs Sud-Ouest Occitanie Réunion, Hôpital Arnaud de Villeneuve, Montpellier, France.
  • 31 Université Montpellier, Unité Inserm U1183, Montpellier, France.
  • 32 Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
  • 33 Stanford Center for Undiagnosed Diseases, Stanford University, Stanford, CA, USA.
  • 34 Memorial Hermann Memorial City Medical Center, Houston, TX, USA.
  • 35 Arnold Palmer Hospital for Children, Orlando, FL, USA.
  • 36 Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA.
  • 37 Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 38 Division of Pediatric Neurology, Columbia University Irving Medical Center, New York, NY, USA.
  • 39 Division of Genetics, St. Luke's Clinic, Boise, ID, USA.
  • 40 Department of Genetics and Genome Sciences, Case Western Reserve University, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
  • 41 Service de Génétique Clinique Guy Fontaine Centre de référence maladies rares Anomalies du dévelopement, Hôpital Jeanne de Flandre Lille, Lille, France.
  • 42 Department of Pediatrics, AI duPont Hospital, DE, Wilmington, USA.
  • 43 Institut de Genetique et de Biologie Moleculaire et Cellulaire, Illkirch-Graffenstaden, Lille, France.
  • 44 Service de Génétique Clinique, Centre de compétence Maladies rares Anomalies du dévelopement, CHU de Poitiers, Poitiers, France.
  • 45 Service de Génétique Clinique Centre de référence maladies rares Anomalies du dévelopement, CHU Amiens-Picardie, Amiens, France.
  • 46 Children's Medical Center, UMass Memorial Medical Center, Worcester, MA, USA.
  • 47 Department of Psychiatry, Queen's University, Kingston, ON, Canada.
  • 48 Division of Clinical & Metabolic Genetics, Hospital for Sick Children, Toronto, ON, Canada.
  • 49 GeneDx, Gaithersburg, MD, USA.
  • 50 Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital, Stanford University, Stanford, CA, USA.
  • 51 Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children's Hospital, San Diego, CA, USA.
  • 52 Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
  • 53 Department of Biosciences, COMSATS University, Islamabad, Pakistan.
  • 54 Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 55 Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 56 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • 57 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
  • 58 CHU de Nantes, Service de génétique médicale, Nantes, France.
  • 59 University of Washington Foundation Board, University of Washington, Seattle, WA, USA.
  • 60 Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA.
PMID: 31723249 DOI: 10.1038/s41436-019-0693-9
Abstract

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292).

Methods: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships.

Results: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among Others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment.

Conclusion: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Keywords

ZNF292; autism spectrum disorders; exome sequencing; intellectual disability; next-generation sequencing.

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