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Original research
SETD1B-associated neurodevelopmental disorder
  1. Alexandra Roston1,
  2. Dan Evans2,
  3. Harinder Gill1,3,
  4. Margaret McKinnon1,
  5. Bertrand Isidor4,
  6. Benjamin Cogné4,5,
  7. Jill Mwenifumbo1,6,
  8. Clara van Karnebeek7,8,
  9. Jianghong An9,
  10. Steven J M Jones9,
  11. Matthew Farrer2,
  12. Michelle Demos10,
  13. Mary Connolly10,
  14. William T Gibson1,
  15. CAUSES Study
  16. EPGEN Study
      1. 1Department of Medical Genetics, The University of British Columbia, Vancouver, British Columbia, Canada
      2. 2Centre for Applied Neurogenetics, The University of British Columbia, Vancouver, British Columbia, Canada
      3. 3Provincial Medical Genetics Program, BC Women’s Hospital and Health Centre, Vancouver, British Columbia, Canada
      4. 4Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, Pays de la Loire, France
      5. 5INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, Frances
      6. 6Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
      7. 7Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology and Metabolism, Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands
      8. 8Department of Pediatrics, Radboud Centre for Mitochondrial Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
      9. 9Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada
      10. 10Division of Neurology, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
      1. Correspondence to Dr Alexandra Roston, Department of Medical Genetics, The University of British Columbia, Vancouver, BC V6T 1Z4, Canada; alexandra.roston{at}


      Background Dysfunction of histone methyltransferases and chromatin modifiers has been implicated in complex neurodevelopmental syndromes and cancers. SETD1B encodes a lysine-specific methyltransferase that assists in transcriptional activation of genes by depositing H3K4 methyl marks. Previous reports of patients with rare variants in SETD1B describe a distinctive phenotype that includes seizures, global developmental delay and intellectual disability.

      Methods Two of the patients described herein were identified via genome-wide and exome-wide testing, with microarray and research-based exome, through the CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) Research Clinic at the University of British Columbia. The third Vancouver patient had clinical trio exome sequencing through Blueprint Genetics. The fourth patient underwent singleton exome sequencing in Nantes, with subsequent recruitment to this cohort through GeneMatcher.

      Results Here we present clinical reports of four patients with rare coding variants in SETD1B that demonstrate a shared phenotype, including intellectual disability, language delay, conserved musculoskeletal findings and seizures that may be treatment-refractory. We include supporting evidence from next-generation sequencing among a cohort of paediatric patients with epilepsy.

      Conclusion Rare coding variants in SETD1B can cause a diagnosable syndrome and could contribute as a risk factor for epilepsy, autism and other neurodevelopmental phenotypes. In the long term, some patients may also be at increased risk for cancers and other complex diseases. Thus, longitudinal studies are required to further elucidate the precise role of SETD1B in neurodevelopmental disorders and other systemic disease.

      • genetics
      • clinical genetics
      • epilepsy and seizures
      • molecular genetics

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      • Collaborators CAUSES study investigators include Shelin Adam, Nick Dragojlovic, Christèle du Souich, Alison M Elliott, Anna Lehman, Larry Lynd, Jill Mwenifumbo, Tanya N Nelson, Clara van Karnebeek and Jan M Friedman (PI). EPGEN study investigators include Shelin Adam, Cyrus Boelman, Corneliu Bolbocean, Sarah E Buerki, Tara Candido, Patrice Eydoux, Daniel M Evans, William T Gibson, Gabriella Horvath, Linda Huh, Tanya N Nelson, Graham Sinclair, Tamsin Tarling, Eric B Toyota, Katelin N Townsend, Margot I Van Allen, Clara van Karnebeek and Suzanne Vercauteren.

      • Contributors As the first author, AR was involved in manuscript writing, data interpretation and creating patient figures. DE and MF performed the statistical analysis of the data and contributed significantly to drafting the manuscript. HG, MM, BI, BC, MD and MC all contributed patient cases and contributed to manuscript revisions. Additionally, MD and MC assisted in initial patient recruitment to the EPGEN study and provided neurological expertise in describing the cases. JM and CvK are investigators in the CAUSES study and contributed to drafting and revision of the manuscript. JA and SJMJ contributed their expertise regarding modelling and interpretation of the SETD1B protein, as well as the creation of figures detailing domain characteristics. As the last author, WTG assisted in data acquisition, interpretation, manuscript writing, figure and table preparation, and overseeing project development. All authors have agreed to be responsible for the accuracy and integrity of this manuscript.

      • Funding The CAUSES study was made possible by a $3 million donation from Mining for Miracles through the BC Children’s Hospital Foundation and is supported by Genome British Columbia, the Provincial Health Services Authority, BC Children’s and Women's Hospitals, the Provincial Medical Genetics Program, BC Children's Hospital Pathology and Laboratory Medicine, and the University of British Columbia. This study was funded by BC Children's Hospital Intramural Funds, Canadian Institutes of Health Research (project grant: PJT-148695, PJT-148830). WTG's salary is supported by the BC Children's Hospital Foundation through their Investigator Grant Award Program (IGAP).

      • Competing interests WTG reports grants from the Canadian Institutes of Health Research, grants from Heart and Stroke Foundation of Canada, and grants from the Rare Disease Foundation. DE is named in a disclosure to the University of British Columbia regarding the creation of software for the annotation and analysis of human genetic variation in the context of disease. Some of the data analyses performed in this paper were done using the data stored and annotated by this software, which is available under a licensing agreement to third parties. MD has received research support from the Rare Disease Foundation and the Alva Foundation.

      • Patient consent for publication Parental/guardian consent obtained.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. Data represented deidentified participant data, available from the CAUSES and EPGEN studies (University of British Columbia).

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