2. Academic Validation
  3. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

  • Genet Med. 2021 Feb;23(2):374-383. doi: 10.1038/s41436-020-00992-z.
Eline A Verberne # 1,  Shuxiang Goh # 2,  Jade England # 3,  Manon van Ginkel 1 4,  Louise Rafael-Croes 4,  Saskia Maas 1,  Abeltje Polstra 1,  Yuri A Zarate 5,  Katherine A Bosanko 5,  Kieran B Pechter 6,  Emma Bedoukian 7,  Kosuke Izumi 7,  Ayeshah Chaudhry 8 9,  Nathaniel H Robin 10,  Megan Boothe 10,  Natalie C Lippa 11,  Vimla Aggarwal 11,  Darryl C De Vivo 12,  Anna Lehman 13,  Causes Study 13,  Sylvia Stockler 14,  Ange-Line Bruel 15,  Bertrand Isidor 16,  Jennifer Lemons 17,  David F Rodriguez-Buritica 17,  Christopher M Richmond 18 19,  Zornitza Stark 18 20,  Pankaj B Agrawal 21,  R Frank Kooy 22,  Marije E C Meuwissen 22 23,  David A Koolen 24,  Rolf Pfundt 24,  Agne Lieden 25 26,  Britt-Marie Anderlid 25 26,  Dagmar Glatz 27,  Marcel M A M Mannens 1,  Madhura Bakshi 2,  Frédérick A Mallette 27,  Mieke M van Haelst # 28,  Philippe M Campeau # 29
Affiliations

Affiliations

  • 1 Department of Clin Genet, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands.
  • 2 Department of Clin Genet, Liverpool Hospital, Sydney, Australia.
  • 3 Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
  • 4 Department of Pediatrics, Dr. Horacio E. Oduber Hospital, Oranjestad, Aruba.
  • 5 Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
  • 6 Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 7 Roberts Individualized Medical Genetics Center and the Division of Hum Genet, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 8 Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, ON, Canada.
  • 9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
  • 10 Department of Genetics, University of Alabama at Birmingham (UAB), Birmingham, AL, USA.
  • 11 Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, USA.
  • 12 Departments of Neurology and Pediatrics, Columbia University Irving Medical Center, New York, NY, USA.
  • 13 Department of Medical Genetics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 14 Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
  • 15 Équipe Génétique des Anomalies du Développement (GAD), CHU Dijon-Bourgogne, Dijon, France.
  • 16 Service de génétique médicale, CHU de Nantes, Nantes, France.
  • 17 Department of Pediatrics, UTHealth McGovern Medical School, Houston, TX, USA.
  • 18 Victorian Clin Genet Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
  • 19 School of Medicine, Griffith University, Gold Coast, QLD, Australia.
  • 20 Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
  • 21 Divisions of Newborn Medicine and Genetics & Genomics, Department of Pediatrics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
  • 22 Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  • 23 Department of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
  • 24 Department of Hum Genet, Radboud Institute for Molecular Life Sciences and Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands.
  • 25 Department of Clin Genet, Karolinska University Hospital, Stockholm, Sweden.
  • 26 Department of molecular medicine and surgery, Karolinska Institutet, Stockholm, Sweden.
  • 27 Département de Médecine, Faculté de médecine, Université de Montréal, and Centre de Recherche de l'Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada.
  • 28 Department of Clin Genet, Amsterdam UMC, Amsterdam Reproduction and Development Research Institute, University of Amsterdam, Amsterdam, The Netherlands. [email protected].
  • 29 Department of Pediatrics, University of Montreal, Montreal, QC, Canada. [email protected].
  • # Contributed equally.
PMID: 33077894 DOI: 10.1038/s41436-020-00992-z
Abstract

Purpose: JARID2, located on chromosome 6p22.3, is a regulator of Histone Methyltransferase complexes that is expressed in human neurons. So far, 13 individuals sharing clinical features including intellectual disability (ID) were reported with de novo heterozygous deletions in 6p22-p24 encompassing the full length JARID2 gene (OMIM 601594). However, all published individuals to date have a deletion of at least one other adjoining gene, making it difficult to determine if JARID2 is the critical gene responsible for the shared features. We aim to confirm JARID2 as a human disease gene and further elucidate the associated clinical phenotype.

Methods: Chromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2.

Results: We report 16 individuals in 15 families with a deletion or single-nucleotide variant in JARID2. Several of these variants are likely to result in haploinsufficiency due to nonsense-mediated messenger RNA (mRNA) decay. All individuals have developmental delay and/or ID and share some overlapping clinical characteristics such as facial features with those who have larger deletions involving JARID2.

Conclusion: We report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene-disease validity for the purpose of diagnostic reporting.

Keywords

JARID2; developmental delay; intellectual disability; neurodevelopment.

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