JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

Eline A. Verberne, Shuxiang Goh, Jade England, Manon van Ginkel, Louise Rafael-Croes, Saskia Maas, Abeltje Polstra, Yuri A. Zarate, Katherine A. Bosanko, Kieran B. Pechter, Emma Bedoukian, Kosuke Izumi, Ayeshah Chaudhry, Nathaniel H. Robin, Megan Boothe, Natalie C. Lippa, Vimla Aggarwal, Darryl C. De Vivo, Anna Lehman, Causes StudySylvia Stockler, Ange Line Bruel, Bertrand Isidor, Jennifer Lemons, David F. Rodriguez-Buritica, Christopher M. Richmond, Zornitza Stark, Pankaj B. Agrawal, R. Frank Kooy, Marije E.C. Meuwissen, David A. Koolen, Rolf Pfundt, Agne Lieden, Britt Marie Anderlid, Dagmar Glatz, Marcel M.A.M. Mannens, Madhura Bakshi, Frédérick A. Mallette, Mieke M. van Haelst*, Philippe M. Campeau

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)374-383
Number of pages10
JournalGenetics in Medicine
Issue number2
Publication statusPublished - Feb 2021

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