TY - JOUR
T1 - Functional Insight into and Refinement of the Genomic Boundaries of the JARID2-Neurodevelopmental Disorder Episignature
AU - van der Laan, Liselot
AU - Rooney, Kathleen
AU - Haghshenas, Sadegheh
AU - Silva, Ananília
AU - McConkey, Haley
AU - Relator, Raissa
AU - Levy, Michael A.
AU - Valenzuela, Irene
AU - Trujillano, Laura
AU - Lasa-Aranzasti, Amaia
AU - Campos, Berta
AU - Castells, Neus
AU - Verberne, Eline A.
AU - Maas, Saskia
AU - Alders, Mariëlle
AU - Mannens, Marcel M. A. M.
AU - van Haelst, Mieke M.
AU - Sadikovic, Bekim
AU - Henneman, Peter
N1 - Funding Information: Funding for this study is provided in part by the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188). Publisher Copyright: © 2023 by the authors.
PY - 2023/9/1
Y1 - 2023/9/1
N2 - JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22–p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22–p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22–p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
AB - JARID2 (Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. JARID2 acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. JARID2 plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving JARID2. For this study, our aim was to determine whether patients with larger deletions spanning beyond JARID2 present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22–p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic JARID2 variants or patients carrying copy number variants, and three patients with JARID2 VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the JARID2-neurodevelopmental syndrome. DNA methylation analysis indicated that JARID2 is the driver gene for aberrant DNA methylation observed in 6p22–p24 microdeletions. In addition, we performed analysis of functional correlation of the JARID2 genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the JARID2 episignature in 6p22–p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by JARID2 is lost.
KW - CNV
KW - DNA methylation
KW - JARID2
KW - episignature
KW - intellectual disability
UR - http://www.scopus.com/inward/record.url?scp=85172807925&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/ijms241814240
DO - https://doi.org/10.3390/ijms241814240
M3 - Article
C2 - 37762546
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 18
M1 - 14240
ER -