JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

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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.

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Fig. 1: Facial appearance of patients with JARID2 deletions and single-nucleotide variants.
Fig. 2: Localization of deletions reported in this study and previously reported JARID2-plus deletions.
Fig. 3: Graphical overview of the JARID2 single-nucleotide variants and deletions.

Change history

  • 22 October 2020

    The original online PDF version of the Article contained figures in monochrome. They now appear in colour in the PDF and HTML versions of the Article.

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Acknowledgements

We thank the families described in this study. Individual 12 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). P.M.C. is supported by awards from the Canadian Institutes of Health Research and the Fonds de la Recherche du Quebec–Santé.

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Correspondence to Mieke M. van Haelst MD or Philippe M. Campeau MD.

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Verberne, E.A., Goh, S., England, J. et al. JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. Genet Med (2020). https://doi.org/10.1038/s41436-020-00992-z

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Keywords

  • JARID2
  • intellectual disability
  • developmental delay
  • neurodevelopment

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