CHD2

Chr 15AD

chromodomain helicase DNA binding protein 2

Also known as: DEE94, EEOC

NCBI Gene: 1106 ENSG00000173575 UniProt: O14647 OMIM: 602119

CHD2 encodes a chromatin remodeling protein that uses its helicase/ATPase domains to modify chromatin structure and regulate gene expression. Mutations cause developmental and epileptic encephalopathy 94, inherited in an autosomal dominant pattern. The gene is highly intolerant to loss-of-function variants, and mutations predominantly cause disease through haploinsufficiency.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The CHD family of proteins is characterized by the presence of chromo (chromatin organization modifier) domains and SNF2-related helicase/ATPase domains. CHD genes alter gene expression possibly by modification of chromatin structure thus altering access of the transcriptional apparatus to its chromosomal DNA template. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.071 OMIM phenotype

Clinical Summary— CHD2

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · 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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.07LOEUF

pLI 1.000

Z-score 9.50

OE 0.03 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.21Z-score

OE missense 0.53 (0.49–0.57)

523 obs / 982.0 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.03 (0.01–0.07)

0≤0.351.4

Missense OE?0.53 (0.49–0.57)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 3 / 111.0Missense obs/exp: 523 / 982.0Syn Z: 0.71

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCHD2-related epileptic encephalopathyLOFAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.2995th %ile

LOF

0.72top 10%

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

LOFprediction above median · 1 literature citation · LOEUF 0.07 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFThe results of this study, in addition to our review of the literature, support a causative role of CHD2 haploinsufficiency in developmental delay, intellectual disability, epilepsy and behavioural problems, with phenotypic variability between individuals.1

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

References