TY - JOUR
T1 - JARID2 haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome
AU - Verberne, Eline A.
AU - Goh, Shuxiang
AU - England, Jade
AU - van Ginkel, Manon
AU - Rafael-Croes, Louise
AU - Maas, Saskia
AU - Polstra, Abeltje
AU - Zarate, Yuri A.
AU - Bosanko, Katherine A.
AU - Pechter, Kieran B.
AU - Bedoukian, Emma
AU - Izumi, Kosuke
AU - Chaudhry, Ayeshah
AU - Robin, Nathaniel H.
AU - Boothe, Megan
AU - Lippa, Natalie C.
AU - Aggarwal, Vimla
AU - De Vivo, Darryl C.
AU - Lehman, Anna
AU - Study, Causes
AU - Stockler, Sylvia
AU - Bruel, Ange Line
AU - Isidor, Bertrand
AU - Lemons, Jennifer
AU - Rodriguez-Buritica, David F.
AU - Richmond, Christopher M.
AU - Stark, Zornitza
AU - Agrawal, Pankaj B.
AU - Kooy, R. Frank
AU - Meuwissen, Marije E.C.
AU - Koolen, David A.
AU - Pfundt, Rolf
AU - Lieden, Agne
AU - Anderlid, Britt Marie
AU - Glatz, Dagmar
AU - Mannens, Marcel M.A.M.
AU - Bakshi, Madhura
AU - Mallette, Frédérick A.
AU - van Haelst, Mieke M.
AU - Campeau, Philippe M.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - developmental delay
KW - intellectual disability
KW - JARID2
KW - neurodevelopment
UR - http://www.scopus.com/inward/record.url?scp=85092694932&partnerID=8YFLogxK
U2 - 10.1038/s41436-020-00992-z
DO - 10.1038/s41436-020-00992-z
M3 - Article
C2 - 33077894
AN - SCOPUS:85092694932
VL - 23
JO - Genetics in Medicine
JF - Genetics in Medicine
SN - 1098-3600
IS - 2
ER -