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JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome

2020; Elsevier BV; Volume: 23; Issue: 2 Linguagem: Inglês

10.1038/s41436-020-00992-z

1530-0366

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

Genomics and Rare Diseases

PurposeJARID2, 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.MethodsChromosome microarray analysis, exome sequencing, and an online matching platform (GeneMatcher) were used to identify individuals with single-nucleotide variants or deletions involving JARID2.ResultsWe 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.ConclusionWe report that JARID2 haploinsufficiency leads to a clinically distinct neurodevelopmental syndrome, thus establishing gene–disease validity for the purpose of diagnostic reporting.