JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

This article has been updated



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.


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


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.


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

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    Li G, Margueron R, Ku M, Chambon P, Bernstein BE, Reinberg D. Jarid2 and PRC2, partners in regulating gene expression. Genes Dev. 2010;24:368–380.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Mysliwiec MR, Carlson CD, Tietjen J, Hung H, Ansari AZ, Lee Y. Jarid2 (Jumonji, AT rich interactive domain 2) regulates NOTCH1 expression via histone modification in the developing heart. J Biol Chem. 2012;287:1235–1241.

    CAS  PubMed  Google Scholar 

  3. 3.

    Pasini D, Cloos PA, Walfridsson J, et al. JARID2 regulates binding of the Polycomb repressive complex 2 to target genes in ES cells. Nature. 2010;464:306–310.

    CAS  PubMed  Google Scholar 

  4. 4.

    Shen X, Kim W, Fujiwara Y, et al. Jumonji modulates polycomb activity and self-renewal versus differentiation of stem cells. Cell. 2009;139:1303–1314.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Peng JC, Valouev A, Swigut T, et al. Jarid2/Jumonji coordinates control of PRC2 enzymatic activity and target gene occupancy in pluripotent cells. Cell. 2009;139:1290–1302.

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Landeira D, Bagci H, Malinowski AR, et al. Jarid2 coordinates nanog expression and PCP/Wnt signaling required for efficient ESC differentiation and early embryo development. Cell Rep. 2015;12:573–586.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Yoon K, Gaiano N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat Neurosci. 2005;8:709–715.

    CAS  PubMed  Google Scholar 

  8. 8.

    Shirato H, Ogawa S, Nakajima K, et al. A jumonji (Jarid2) protein complex represses cyclin D1 expression by methylation of histone H3-K9. J Biol Chem. 2009;284:733–739.

    CAS  PubMed  Google Scholar 

  9. 9.

    Jung J, Mysliwiec MR, Lee Y. Roles of JUMONJI in mouse embryonic development. Dev Dyn. 2005;232:21–32.

    CAS  PubMed  Google Scholar 

  10. 10.

    Berge-Lefranc JL, Jay P, Massacrier A, et al. Characterization of the human jumonji gene. Hum Mol Genet. 1996;5:1637–1641.

    CAS  PubMed  Google Scholar 

  11. 11.

    Yuen RK, Merico D, Cao H, et al. Genome-wide characteristics of de novo mutations in autism. NPJ Genom Med. 2016;1:160271–1602710.

    PubMed  Google Scholar 

  12. 12.

    De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–215.

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014;506:179–184.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Scapoli L, Martinelli M, Pezzetti F, et al. Expression and association data strongly support JARID2 involvement in nonsyndromic cleft lip with or without cleft palate. Hum Mutat. 2010;31:794–800.

    CAS  PubMed  Google Scholar 

  15. 15.

    Messetti AC, Machado RA, de Oliveira CE, et al. Brazilian multicenter study of association between polymorphisms in CRISPLD2 and JARID2 and nonsyndromic oral clefts. J Oral Pathol Med. 2017;46:232–239.

    CAS  PubMed  Google Scholar 

  16. 16.

    Davies AF, Olavesen MG, Stephens RJ, et al. A detailed investigation of two cases exhibiting characteristics of the 6p deletion syndrome. Hum Genet. 1996;98:454–459.

    CAS  PubMed  Google Scholar 

  17. 17.

    Davies AF, Mirza G, Sekhon G, et al. Delineation of two distinct 6p deletion syndromes. Hum Genet. 1999;104:64–72.

    CAS  PubMed  Google Scholar 

  18. 18.

    Zirn B, Hempel M, Hahn A, et al. Polyneuropathy, scoliosis, tall stature, and oligodontia represent novel features of the interstitial 6p deletion phenotype. Am J Med Genet A. 2008;146:2960–2965.

    Google Scholar 

  19. 19.

    van Swaay E, Beverstock GC, van de Kamp JJ. A patient with an interstitial deletion of the short arm of chromosome 6. Clin Genet 1988;33:95–101.

    CAS  PubMed  Google Scholar 

  20. 20.

    Baroy T, Misceo D, Stromme P, et al. Haploinsufficiency of two histone modifier genes on 6p22.3, ATXN1 and JARID2, is associated with intellectual disability. Orphanet J Rare Dis. 2013;8:3.

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Celestino-Soper PB, Skinner C, Schroer R, et al. Deletions in chromosome 6p22.3-p24.3, including ATXN1, are associated with developmental delay and autism spectrum disorders. Mol Cytogenet. 2012;5:17.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Di Benedetto D, Di Vita G, Romano C, et al. 6p22.3 deletion: report of a patient with autism, severe intellectual disability and electroencephalographic anomalies. Mol Cytogenet. 2013;6:4.

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Sobreira N, Schiettecatte F, Valle D, Hamosh A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat. 2015;36:928–930.

    PubMed  PubMed Central  Google Scholar 

  24. 24.

    Petrovski S, Aggarwal V, Giordano JL, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758–767.

    CAS  PubMed  Google Scholar 

  25. 25.

    Zhu X, Petrovski S, Xie P, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17:774–781.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Nambot S, Thevenon J, Kuentz P, et al. Clinical whole-exome sequencing for the diagnosis of rare disorders with congenital anomalies and/or intellectual disability: substantial interest of prospective annual reanalysis. Genet Med. 2018;20:645–654.

    CAS  PubMed  Google Scholar 

  27. 27.

    Baker SW, Murrell JR, Nesbitt AI, et al. Automated clinical exome reanalysis reveals novel diagnoses. J Mol Diagn. 2019;21:38–48.

    CAS  PubMed  Google Scholar 

  28. 28.

    Gibson KM, Nesbitt A, Cao K, et al. Novel findings with reassessment of exome data: implications for validation testing and interpretation of genomic data. Genet Med. 2018;20:329–336.

    PubMed  Google Scholar 

  29. 29.

    Wu C, Devkota B, Evans P, et al. Rapid and accurate interpretation of clinical exomes using Phenoxome: a computational phenotype-driven approach. Eur J Hum Genet. 2019;27:612–620.

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Lelieveld SH, Reijnders MR, Pfundt R, et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. 2016;19:1194–1196.

    CAS  PubMed  Google Scholar 

  31. 31.

    Tucker T, Zahir FR, Griffith M, et al. Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes. Eur J Hum Genet. 2014;22:792–800.

    CAS  PubMed  Google Scholar 

  32. 32.

    Zahir FR, Tucker T, Mayo S, et al. Intragenic CNVs for epigenetic regulatory genes in intellectual disability: survey identifies pathogenic and benign single exon changes. Am J Med Genet A. 2016;170:2916–2926.

    CAS  PubMed  Google Scholar 

  33. 33.

    Shaikh TH, Conlin LK, Geiger EA, et al. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res. 2009;19:1682–1690.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wong KK, deLeeuw RJ, Dosanjh NS, et al. A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet. 2007;80:91–104.

    CAS  PubMed  Google Scholar 

  35. 35.

    Alvarado DM, Buchan JG, Frick SL, Herzenberg JE, Dobbs MB, Gurnett CA. Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development. Eur J Hum Genet. 2013;21:373–380.

    CAS  PubMed  Google Scholar 

  36. 36.

    Martinez F, Caro-Llopis A, Rosello M, et al. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J Med Genet. 2017;54:87–92.

    CAS  PubMed  Google Scholar 

  37. 37.

    Abidi F, Miano M, Murray J, Schwartz C. A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet. 2007;72:19–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Adam MP, Banka S, Bjornsson HT, et al. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019;56:89–95.

    PubMed  Google Scholar 

  39. 39.

    Stolerman ES, Francisco E, Stallworth JL, et al. Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features. Am J Med Genet A. 2019;179:1276–1286.

    CAS  PubMed  Google Scholar 

  40. 40.

    Najmabadi H, Hu H, Garshasbi M, et al. Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature. 2011;478:57–63.

    CAS  PubMed  Google Scholar 

  41. 41.

    Quinodoz M, Royer-Bertrand B, Cisarova K, Di Gioia SA, Superti-Furga A, Rivolta C. DOMINO: using machine learning to predict genes associated with dominant disorders. Am J Hum Genet. 2017;101:623–629.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references


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.

Author information



Corresponding authors

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

Ethics declarations


The authors declare no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation


  • JARID2
  • intellectual disability
  • developmental delay
  • neurodevelopment