CHD1

Chr 5AD

chromodomain helicase DNA binding protein 1

Also known as: CHD-1, PILBOS

NCBI Gene: 1105 ENSG00000153922 UniProt: O14646 OMIM: 602118

The CHD1 protein functions as a chromatin remodeler that uses its helicase/ATPase domains to alter chromatin structure and regulate gene expression by modifying access of transcriptional machinery to DNA. Loss-of-function mutations cause Pilarowski-Bjornsson syndrome through an autosomal dominant inheritance pattern. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

LOFmechanismADLOEUF 0.161 OMIM phenotype

Clinical Summary— CHD1

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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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ClinVar Variants

26 unique Pathogenic / Likely Pathogenic· 360 VUS of 500 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.16LOEUF

pLI 1.000

Z-score 8.28

OE 0.09 (0.06–0.16)

Highly constrained

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

Missense Constraint

4.21Z-score

OE missense 0.59 (0.55–0.64)

507 obs / 852.9 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.09 (0.06–0.16)

0≤0.351.4

Missense OE0.59 (0.55–0.64)

0≤0.61.4

Synonymous OE0.96

0≤1.21.6

LoF obs/exp: 9 / 96.9Missense obs/exp: 507 / 852.9Syn Z: 0.53

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCHD1-related neurodevelopment disorderLOFAD

0.3196th %ile

GOF

0.2994th %ile

LOF

0.74top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 23% of P/LP variants are LoF · LOEUF 0.16

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNOur results suggest that variants in CHD1 can lead to diverse phenotypic outcomes; however, the neurodevelopmental phenotype appears to be limited to patients with missense variants, which is compatible with a dominant negative mechanism of disease.PMID:28866611

GOFBy a series of domain-swapping and mutagenesis experiments, we identify Pro16 of E-cadherin as a residue critical for specificity: a Pro->Glu substitution in human E-cadherin totally abrogates interaction, whereas a Glu->Pro substitution in mouse E-cadherin results in a complete gain of function.PMID:10406800

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