Phenotypic expansion and variable expressivity in individuals with <i>JARID2</i>‐related intellectual disability: A case series

Cadieux-Dion, Maxime; Farrow, Emily; Thiffault, Isabelle; Cohen, Ana S A; Welsh, Holly; Bartik, Lauren; Schwager, Caitlin; Engleman, Kendra; Zhou, Dihong; Zhang, Lei; Repnikova, Elena; Amudhavalli, Shivarajan; Saunders, Carol J.

doi:10.1111/cge.14149

Cited by 3 publications

(6 citation statements)

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“…JARID2 (Jumonji, AT Rich Interactive Domain 2; OMIM 601594) haploinsufficiency has been associated with a clinically distinct neurodevelopmental syndrome [ 1 , 2 , 3 ]. It is characterized by developmental delay, cognitive impairment (ranging from borderline intellectual functioning to severe intellectual disability), hypotonia, autistic features and behavior abnormalities.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

Verberne

Laan

Haghshenas

et al. 2022

IJMS

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JARID2 (Jumonji, AT Rich Interactive Domain 2) pathogenic variants cause a neurodevelopmental syndrome, that is characterized by developmental delay, cognitive impairment, hypotonia, autistic features, behavior abnormalities and dysmorphic facial features. JARID2 encodes a transcriptional repressor protein that regulates the activity of various histone methyltransferase complexes. However, the molecular etiology is not fully understood, and JARID2-neurodevelopmental syndrome may vary in its typical clinical phenotype. In addition, the detection of variants of uncertain significance (VUSs) often results in a delay of final diagnosis which could hamper the appropriate care. In this study we aim to detect a specific and sensitive DNA methylation signature for JARID2-neurodevelopmental syndrome. Peripheral blood DNA methylation profiles from 56 control subjects, 8 patients with (likely) pathogenic JARID2 variants and 3 patients with JARID2 VUSs were analyzed. DNA methylation analysis indicated a clear and robust separation between patients with (likely) pathogenic variants and controls. A binary model capable of classifying patients with the JARID2-neurodevelopmental syndrome was constructed on the basis of the identified episignature. Patients carrying VUSs clustered with the control group. We identified a distinct DNA methylation signature associated with JARID2-neurodevelopmental syndrome, establishing its utility as a biomarker for this syndrome and expanding the EpiSign diagnostic test.

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Section: Introductionmentioning

confidence: 99%

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

Verberne

Laan

Haghshenas

et al. 2022

IJMS

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“…This effect is assumed to be similar to patients that have whole-gene deletions of JARID2 [ 6 ]. Taken together, with the similarity in phenotype of case 3 in comparison with the others and the positive signature, this may indicate that JARID2 is a critical gene within the 6p22–p24 microdeletion region, and that the aberrant methylation is driven by genetic variations involving JARID2 [ 1 , 2 , 4 , 5 , 13 ].…”

Section: Discussionmentioning

confidence: 78%

“…One possible explanation is that this particular deletion has a distinct effect on DNA methylation across the genome, causing it not to align with cases that have more similar functional consequences. A less likely case is that it could also suggest that the JARID2 episignature lacks complete penetrance in all cases [ 1 ]. Further research is necessary to shed light on this unexpected finding.…”

Section: Discussionmentioning

confidence: 99%

“…JARID2 (OMIM; #601594) haploinsufficiency (DIDDF, OMIM; #620098) leads to a clinically distinct neurodevelopmental syndrome characterized by intellectual disability (ID), developmental delay (DD), autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features such as high anterior hairline, deeply set eyes, depressed nasal bridge, full lips, broad forehead, and bulbous nasal tip [ 1 , 2 ]. JARID2 is located at chromosome region 6p22.3.…”

Section: Introductionmentioning

confidence: 99%

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Functional Insight into and Refinement of the Genomic Boundaries of the JARID2-Neurodevelopmental Disorder Episignature

van der Laan,

Rooney,

Haghshenas

et al. 2023

IJMS

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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.

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“…Here we show that KOLF2.1J iPSCs carry at least 5 small CNVs (<1Mbp), two of which cause DTNBP1, JARID2 and ASTN2 haploinsufficiency. Given the association of these genes with neurodevelopmental disorders [18][19][20][21][22][23][24][25][26][27] and constraints for disruptive variants in human genomes [28][29][30] our work uncovers that KOLF2.1J iPSCs carry genetic variants that may affect the interpretation of developmental and neural cell phenotypes. Our work further highlights the need for the inclusion of structural variants in genome sequencing analyses of iPSC lines and the creation of a catalogue of reference iPSCs which shall include a comprehensive characterization of genes predicted to be intolerant to disruptive variation during human development.…”

Section: Introductionmentioning

confidence: 97%

High density SNP array and reanalysis of genome sequencing uncovers CNVs associated with neurodevelopmental disorders in KOLF2.1J iPSCs

Gracia-Diaz,

Perdomo,

Khan

et al. 2023

Preprint

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The KOLF2.1J iPSC line was recently proposed as a reference iPSC to promote the standardization of research studies in the stem cell field. Due to overall good performance differentiating to neural cell lineages, high gene editing efficiency, and absence of genetic variants associated to neurological disorders KOLF2.1J iPSC line was particularly recommended for neurodegenerative disease modeling. However, our work uncovers that KOLF2.1J hPSCs carry heterozygous small copy number variants (CNVs) that cause DTNBP1, JARID2 and ASTN2 haploinsufficiencies, all of which are associated with neurological disorders. We further determine that these CNVs arose in vitro over the course of KOLF2.1J iPSC generation from a healthy donor-derived KOLF2 iPSC line and affect the expression of DNTBP1, JARID2 and ASTN2 proteins in KOLF2.1J iPSCs and neural progenitors. Therefore, our study suggests that KOLF2.1J iPSCs carry genetic variants that may be deleterious for neural cell lineages. This data is essential for a careful interpretation of neural cell studies derived from KOLF2.1J iPSCs and highlights the need for a catalogue of iPSC lines that includes a comprehensive genome characterization analysis.

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Phenotypic expansion and variable expressivity in individuals with JARID2‐related intellectual disability: A case series

Cited by 3 publications

References 10 publications

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

DNA Methylation Signature for JARID2-Neurodevelopmental Syndrome

Functional Insight into and Refinement of the Genomic Boundaries of the JARID2-Neurodevelopmental Disorder Episignature

High density SNP array and reanalysis of genome sequencing uncovers CNVs associated with neurodevelopmental disorders in KOLF2.1J iPSCs

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