CHD1

Chr 5

chromodomain helicase DNA binding protein 1

Also known as: CHD-1, PILBOS

NCBI Gene: 1105 ENSG00000153922 UniProt: O14646

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.

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. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.16

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

13 unique Pathogenic / Likely Pathogenic· 358 VUS of 485 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.09 (0.06–0.16)

0≤0.351.4

Missense OE?0.59 (0.55–0.64)

0≤0.61.4

Synonymous OE?0.96

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

This gene — mechanism propensity

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 · 62% 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.1

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.2

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

References

ClinVar Variant Classifications

485 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic8

VUS358

Likely Benign56

Benign10

Conflicting11

Pathogenic

Likely Pathogenic

358

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	2	0	0	5
Likely Pathogenic	5	2	1	0	8
VUS	38	300	18	2	358
Likely Benign	2	14	3	37	56
Benign	0	6	2	2	10
Conflicting	—				11
Total	48	324	24	41	448

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap CHD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →