ZC4H2

protein-coding

zinc finger C4H2-type containing, the group of Zinc fingers

Gene summary

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]

Previous symbols:

KIAA1166
WWS
MCS
MRXS4

MANE transcript

NM_018684.4

Inheritance

ClinVar variants

P:65U:106B:46

Top phenotype

Wieacker-Wolff syndrome; Wieacker-Wolff syndrome, female-restricted

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:64,915,802-65,034,713

External References & Databases

Ensembl (ENSG00000126970)

Transcript & Mutation Effects

hg38 • Region Span ~118.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Wieacker-Wolff syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010758

Submitter: Labcorp Genetics (formerly Invitae)

Wieacker-Wolff syndrome, female-restrictedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0026762

Submitter: G2P

X-linked syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0020119

Submitter: ClinGen

*ZC4H2* was first reported in relation to X-linked syndromic intellectual disability in 2013 (Hirata et al., PMID: 23623388). *ZC4H2*-associated disorders include Wieacker-Wolff syndrome and Miles-Carpenter syndrome. Individuals with *ZC4H2* variants present with developmental delay, intellectual disability, arthrogryposis multiplex congenita, hypo-/akinesia, facial dysmorphism, and skeletal abnormalities (Frints et al., 2019, PMID: 31206972). Variants in this gene have been reported in at least 33 probands in 3 publications (PMIDs: 23623388, 26056227, 31206972). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Variants in affected males are mostly inherited missense and are likely hypomorphic alleles, whereas female patients have *de novo* loss-of-function variants, which are likely lethal in males (PMID: 31206972). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by phenotype characterization and rescue experiments in a zebrafish model. In summary, there is definitive evidence supporting the relationship between *ZC4H2* and X-linked syndromic intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 7, 2020 (SOP Version 7).

Wieacker-Wolff syndrome, female-restrictedDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0026762

Submitter: Ambry Genetics

Wieacker-Wolff syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010758

Submitter: PanelApp Australia

Wieacker-Wolff syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010758

Submitter: Orphanet

Wieacker-Wolff syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010758

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Wieacker-Wolff syndrome; Wieacker-Wolff syndrome, female-restrictedXL

Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 23623388; 26056227; 28345801; 31206972

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ZC4H2 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 150

Wieacker-Wolff syndromeTotal: 43

Inborn genetic diseasesTotal: 42

Wieacker-Wolff syndrome, female-restrictedTotal: 30

not specifiedTotal: 13

ZC4H2-related disorderTotal: 11

Wieacker-Wolff syndrome (spectrum)Total: 3

ZC4H2-related X-linked intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018684.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	6 clinvar	34 clinvar	4 clinvar	46
missense	9 clinvar	17 clinvar	92 clinvar	6 clinvar	2 clinvar	126
nonsense	7 clinvar	5 clinvar	2 clinvar			14
start loss	1 clinvar		1 clinvar			2
frameshift	9 clinvar	8 clinvar	2 clinvar			19
splice donor/acceptor (+/-2bp)	3 clinvar	4 clinvar	3 clinvar			10
Total	29	36	106	40	6	217

Highest pathogenic variant AF is 0.000008934714

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018684.4	RefSeq	NP_061154.1	5	MANE Select
ENST00000374839.8	Ensembl	ENSP00000363972.3	5	MANE Select
NM_001178032.3	RefSeq	NP_001171503.1	4	Standard
NM_001178033.3	RefSeq	NP_001171504.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
zc4h2	Danio rerio	Structure: motor neuron Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

zc4h2

Danio rerio

Structure: motor neuron

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

nervous system development
neuromuscular junction development
spinal cord motor neuron differentiation
positive regulation of neuron differentiation

Molecular Function

protein binding
metal ion binding

Cellular Component

nucleus
cytoplasm
cell junction
postsynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374839
Coding exons: 5
Length: 118344
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.51	47	86.6	0.543	0.00000694	1487
Missense (PolyPhen)		10	30.128	0.33192		481
Synonymous	-1.42	43	32.7	1.32	0.00000251	405
Loss of Function	2.57	0	7.68	0.00	5.54e-7	139

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in interneurons differentiation (PubMed:26056227). Involved in neuronal development and in neuromuscular junction formation. {ECO:0000269|PubMed:23623388, ECO:0000269|PubMed:26056227}.;

Recessive Scores

pRec: 0.113

Intolerance Scores

LoFtool: 0.0870
RVIS EVS: -0.03
RVIS percentile EVS: 51.4

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium