ZC4H2

Chr XXLRXLD

zinc finger C4H2-type containing

Also known as: HCA127, KIAA1166, MCS, MRXS4, WRWF, WRWFFR, WWS

NCBI Gene: 55906 ENSG00000126970 UniProt: Q9NQZ6 OMIM: 300897

This gene encodes a zinc finger protein that regulates interneuron differentiation and neuromuscular junction formation during neuronal development. Mutations cause Wieacker-Wolff syndrome, characterized by intellectual disability and neuromuscular abnormalities, with X-linked inheritance that can affect both males and females. The gene is highly constrained against loss-of-function variants (pLI 0.91, LOEUF 0.39), indicating that functional copies are essential for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the zinc finger domain-containing protein family. This family member has a C-terminal zinc finger domain that is characterized by four cysteine residues and two histidine residues, and it also includes a coiled-coil region. This protein has been detected as an autoantigen in hepatocellular carcinoma patients. This gene has been identified as a potential candidate for X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLR/XLDLOEUF 0.392 OMIM phenotypes

Clinical Summary— ZC4H2

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

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 0.91). 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?

0.39LOEUF

pLI 0.908

Z-score 2.57

OE 0.00 (0.00–0.39)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.51Z-score

OE missense 0.54 (0.43–0.69)

47 obs / 86.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.39)

0≤0.351.4

Missense OE?0.54 (0.43–0.69)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 0 / 7.7Missense obs/exp: 47 / 86.6Syn Z: -1.42

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveZC4H2-related arthrogryposis multiplex congenita and intellectual disabilityLOFmonoallelic_X_heterozygous

definitiveZC4H2-related arthrogryposis multiplex congenita and intellectual disabilityLOFXLR

This gene — mechanism propensity

0.3793th %ile

GOF

0.4777th %ile

LOF

0.71top 10%

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

LOFprediction above median · LOEUF 0.39 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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