JARID2

Chr 6AD

jumonji and AT-rich interaction domain containing 2

ENSG00000008083 UniProt: Q92833 OMIM: 601594

The JARID2 protein functions as a DNA-binding transcriptional repressor that recruits the Polycomb repressive complex 2 (PRC2) to target genes, playing essential roles in embryonic development including heart and liver development, neural tube fusion, and hematopoiesis. Mutations cause autosomal dominant developmental delay with variable intellectual disability and dysmorphic facies. This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.19), indicating that most loss-of-function mutations are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis (PubMed:20075857). Acts as an accessory subunit for the core PRC2 (Polycomb repressive complex 2) complex, which mediates histone H3K27 (H3K27me3) trimethylation on chromatin (PubMed:20075857, PubMed:29499137, PubMed:31959557). Binds DNA and mediates the recruitment of the PRC2 complex to target genes in embryonic stem cells, thereby playing a key role in stem cell differentiation and normal embryonic development (PubMed:20075857). In cardiac cells, it is required to repress expression of cyclin-D1 (CCND1) by activating methylation of 'Lys-9' of histone H3 (H3K9me) by the GLP1/EHMT1 and G9a/EHMT2 histone methyltransferases (By similarity). Also acts as a transcriptional repressor of ANF via its interaction with GATA4 and NKX2-5 (By similarity). Participates in the negative regulation of cell proliferation signaling (By similarity). Does not have histone demethylase activity (By similarity)

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.191 OMIM phenotype

Clinical Summary— JARID2

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Gene-Disease Validity (ClinGen)

developmental delay with variable intellectual disability and dysmorphic facies · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.19LOEUF

pLI 1.000

Z-score 6.31

OE 0.09 (0.05–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.69Z-score

OE missense 0.73 (0.68–0.78)

575 obs / 787.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.19)

0≤0.351.4

Missense OE?0.73 (0.68–0.78)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 55.9Missense obs/exp: 575 / 787.1Syn Z: -2.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongJARID2-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.19100th %ile

GOF

0.1999th %ile

LOF

0.84top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.19

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.