Wieacker-Wolff syndrome, female-restricted

Summary

Wieacker-Wolff syndrome, female-restricted (MONDO:0026762) is a disease caused by ZC4H2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ZC4H2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 30

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Wieacker-Wolff syndrome, female-restricted
Mondo ID	MONDO:0026762
OMIM	301041
DOID	DOID:0061015
UMLS	C5393303
MedGen	1715791
GARD	0025489
Is cancer (heuristic)	no

Also known as: Wieacker-Wolff syndrome, female-restricted, X-linked dominant · WRWFFR

Data availability: 30 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arthrogryposis multiplex congenita › Wieacker-Wolff syndrome (spectrum) › Wieacker-Wolff syndrome, female-restricted

Related subtypes (1): Wieacker-Wolff syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

30 retrieved; paginated sample, class counts are floors:

11 pathogenic, 10 likely pathogenic, 5 uncertain significance, 3 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3571456	GRCh38/hg38 Xq11.2(chrX:64951692-65166933)x1	ZC3H12B	Pathogenic	criteria provided, single submitter
978034	NC_000023.11:g.64951692_65166933del	ZC3H12B	Pathogenic	criteria provided, single submitter
1164068	NM_018684.4(ZC4H2):c.575G>A (p.Cys192Tyr)	ZC4H2	Pathogenic	no assertion criteria provided
1804075	NM_018684.4(ZC4H2):c.172G>T (p.Glu58Ter)	ZC4H2	Pathogenic	criteria provided, single submitter
2582376	NM_018684.4(ZC4H2):c.388del (p.Leu130fs)	ZC4H2	Pathogenic	criteria provided, single submitter
3899329	NM_018684.4(ZC4H2):c.442G>T (p.Glu148Ter)	ZC4H2	Pathogenic	criteria provided, single submitter
429826	NM_018684.4(ZC4H2):c.199C>T (p.Arg67Ter)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
432364	NM_018684.4(ZC4H2):c.592C>T (p.Arg198Trp)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
50981	NM_018684.4(ZC4H2):c.593G>A (p.Arg198Gln)	ZC4H2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834094	NM_018684.4(ZC4H2):c.225+2T>C	ZC4H2	Pathogenic	no assertion criteria provided
834096	NM_018684.4(ZC4H2):c.275_276del (p.Glu92fs)	ZC4H2	Pathogenic	no assertion criteria provided
834098	NC_000023.10:g.(?64166588)(64361318_?)del	ZC4H2	Pathogenic	no assertion criteria provided
834099	NM_018684.4(ZC4H2):c.426G>A (p.Trp142Ter)	ZC4H2	Pathogenic	no assertion criteria provided
834100	NM_018684.4(ZC4H2):c.67C>T (p.Gln23Ter)	ZC4H2	Pathogenic	no assertion criteria provided
1527923	NM_018684.4(ZC4H2):c.592C>G (p.Arg198Gly)	ZC4H2	Likely pathogenic	criteria provided, single submitter
1723185	NM_018684.4(ZC4H2):c.566G>C (p.Cys189Ser)	ZC4H2	Likely pathogenic	criteria provided, single submitter
3376881	NM_018684.4(ZC4H2):c.398+1_398+3del	ZC4H2	Likely pathogenic	criteria provided, single submitter
3899255	NM_018684.4(ZC4H2):c.616T>C (p.Cys206Arg)	ZC4H2	Likely pathogenic	criteria provided, single submitter
3899336	NM_018684.4(ZC4H2):c.561+2T>C	ZC4H2	Likely pathogenic	criteria provided, single submitter
422398	NM_018684.4(ZC4H2):c.617G>T (p.Cys206Phe)	ZC4H2	Likely pathogenic	criteria provided, single submitter
4292402	NM_018684.4(ZC4H2):c.544C>T (p.Gln182Ter)	ZC4H2	Likely pathogenic	criteria provided, single submitter
4292763	NM_018684.4(ZC4H2):c.455del (p.Pro152fs)	ZC4H2	Likely pathogenic	criteria provided, single submitter
4813338	NM_018684.4(ZC4H2):c.599C>A (p.Ala200Glu)	ZC4H2	Likely pathogenic	criteria provided, single submitter
4819337	NM_018684.4(ZC4H2):c.566G>T (p.Cys189Phe)	ZC4H2	Likely pathogenic	criteria provided, single submitter
1064559	NM_018684.4(ZC4H2):c.246A>C (p.Gln82His)	ZC4H2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2431957	NM_018684.4(ZC4H2):c.290_292del (p.Leu97del)	ZC4H2	Uncertain significance	criteria provided, single submitter
2584832	NM_018684.4(ZC4H2):c.269T>C (p.Leu90Pro)	ZC4H2	Uncertain significance	criteria provided, single submitter
2585507	NM_018684.4(ZC4H2):c.218_220del (p.Ile73del)	ZC4H2	Uncertain significance	criteria provided, single submitter
2671709	NM_018684.4(ZC4H2):c.406G>A (p.Glu136Lys)	ZC4H2	Uncertain significance	criteria provided, multiple submitters, no conflicts
587852	NM_018684.4(ZC4H2):c.432A>G (p.Thr144=)	ZC4H2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ZC4H2	Definitive	X-linked	Wieacker-Wolff syndrome, female-restricted	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ZC4H2	Orphanet:3454	Wieacker-Wolff syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ZC4H2	HGNC:24931	ENSG00000126970	Q9NQZ6	Zinc finger C4H2 domain-containing protein	gencc,clinvar
ZC3H12B	HGNC:17407	ENSG00000102053	Q5HYM0	Probable ribonuclease ZC3H12B	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ZC4H2	Zinc finger C4H2 domain-containing protein	Plays a role in interneurons differentiation.
ZC3H12B	Probable ribonuclease ZC3H12B	May function as RNase and regulate the levels of target RNA species.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ZC4H2	Transcription factor	no		Znf-C4H2, ZF_C4H2
ZC3H12B	Transcription factor	no		Znf_CCCH, RNase_Zc3h12_NYN, Rege-1_UBA-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
embryo	1
ganglionic eminence	1
prefrontal cortex	1
primordial germ cell in gonad	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ZC4H2	196	ubiquitous	yes	ganglionic eminence, cortical plate, embryo
ZC3H12B	177		marker	tibialis anterior, prefrontal cortex, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ZC4H2	954
ZC3H12B	271

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZC4H2	Q9NQZ6	1
ZC3H12B	Q5HYM0	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 2 evidence-associated genes (0 with Reactome annotation).

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of transcription regulatory region DNA binding	1	4213.0×	0.001	ZC4H2
noradrenergic neuron development	1	3370.4×	0.001	ZC4H2
spinal cord motor neuron differentiation	1	936.2×	0.003	ZC4H2
obsolete positive regulation of DNA-binding transcription factor activity	1	601.9×	0.003	ZC4H2
neuromuscular junction development	1	526.6×	0.003	ZC4H2
protein monoubiquitination	1	343.9×	0.004	ZC4H2
positive regulation of neuron differentiation	1	198.3×	0.006	ZC4H2
nervous system development	1	45.9×	0.022	ZC4H2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ZC4H2	0	0
ZC3H12B	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZC4H2, ZC3H12B

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ZC4H2	0	—
ZC3H12B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.