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
  • 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.