ZC4H2

Summary

ZC4H2 (zinc finger C4H2-type containing, HGNC:24931) is a protein-coding gene on chromosome Xq11.2, encoding Zinc finger C4H2 domain-containing protein (Q9NQZ6). Plays a role in interneurons differentiation. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 55906 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 267 total — 33 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 86
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018684

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24931
Approved symbol	ZC4H2
Name	zinc finger C4H2-type containing
Location	Xq11.2
Locus type	gene with protein product
Status	Approved
Aliases	HCA127
Ensembl gene	ENSG00000126970
Ensembl biotype	protein_coding
OMIM	300897
Entrez	55906

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 5 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000337990, ENST00000374839, ENST00000447788, ENST00000476032, ENST00000488608, ENST00000488831, ENST00000492653, ENST00000703133, ENST00000703136

RefSeq mRNA: 4 — MANE Select: NM_018684 NM_001178032, NM_001178033, NM_001243804, NM_018684

CCDS: CCDS14380, CCDS55431, CCDS55432

Canonical transcript exons

ENST00000374839 — 5 exons

Exon	Start	End
ENSE00001464810	64976325	64976450
ENSE00001907590	64915807	64917896
ENSE00003605433	64921817	64921988
ENSE00003647354	64920081	64920253
ENSE00003647791	64919042	64919204

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 93.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.3000 / max 442.4410, expressed in 1483 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199483	4.9117	1235
199487	3.0191	958
199484	0.9348	537
199482	0.8467	466
199485	0.2624	116
199486	0.1867	90
199480	0.1386	51

Top tissues by expression

270 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	93.10	gold quality
cortical plate	UBERON:0005343	89.89	gold quality
embryo	UBERON:0000922	87.38	gold quality
ventricular zone	UBERON:0003053	86.68	gold quality
prefrontal cortex	UBERON:0000451	82.34	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.22	gold quality
popliteal artery	UBERON:0002250	80.87	gold quality
tibial artery	UBERON:0007610	80.86	gold quality
lower esophagus muscularis layer	UBERON:0035833	80.31	gold quality
lower esophagus	UBERON:0013473	80.27	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	79.95	gold quality
aorta	UBERON:0000947	79.88	gold quality
stromal cell of endometrium	CL:0002255	79.87	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.83	gold quality
descending thoracic aorta	UBERON:0002345	79.56	gold quality
islet of Langerhans	UBERON:0000006	79.36	gold quality
left adrenal gland	UBERON:0001234	79.08	gold quality
right adrenal gland	UBERON:0001233	79.00	gold quality
left ovary	UBERON:0002119	78.91	gold quality
right ovary	UBERON:0002118	78.90	gold quality
right adrenal gland cortex	UBERON:0035827	78.82	gold quality
body of uterus	UBERON:0009853	78.78	gold quality
thoracic aorta	UBERON:0001515	78.71	gold quality
left adrenal gland cortex	UBERON:0035825	78.68	gold quality
spinal cord	UBERON:0002240	78.61	gold quality
ascending aorta	UBERON:0001496	78.60	gold quality
adenohypophysis	UBERON:0002196	78.59	gold quality
anterior cingulate cortex	UBERON:0009835	78.31	gold quality
left coronary artery	UBERON:0001626	78.27	gold quality
neocortex	UBERON:0001950	78.25	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.05

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

123 targeting ZC4H2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-34B-5P	99.78	67.56	1175

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• ZC4H2 mutations are associated with arthrogryposis multiplex congenita and intellectual disability through impairment of central and peripheral synaptic plasticity. (PMID:23623388)
• ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons (PMID:26056227)
• The present patient confirms that female carriers can also be severely affected. Systematic clinical investigations of both males and females are needed to define the variety in nature and severity of phenotypes related to ZC4H2 variants. (PMID:28345801)
• Study reports on the genetic and clinical findings of 23 novel families and simplex cases of patients with arthrogryposis multiplex congenita (AMC). Deleterious inherited or de novo ZC4H2 variants were identified in males and females, including de novo partial ZC4H2 micro-deletions present in affected females only. (PMID:31206972)
• The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane. (PMID:32443528)
• A 7-year old female with arthrogryposis multiplex congenita, Duane retraction syndrome, and Marcus Gunn phenomenon due to a ZC4H2 gene mutation: a clinical presentation of the Wieacker-Wolff syndrome. (PMID:33949289)
• Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression. (PMID:35040952)
• Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord. (PMID:36250278)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	zc4h2	ENSDARG00000015314
mus_musculus	Zc4h2	ENSMUSG00000035062
rattus_norvegicus	Zc4h2	ENSRNOG00000056735
drosophila_melanogaster	CG13001	FBGN0030806
caenorhabditis_elegans		WBGENE00014152
caenorhabditis_elegans		WBGENE00014153

Protein

Protein identifiers

Zinc finger C4H2 domain-containing protein — Q9NQZ6 (reviewed: Q9NQZ6)

Alternative names: Hepatocellular carcinoma-associated antigen 127

All UniProt accessions (4): Q9NQZ6, A0A8V8TQM8, A0A8V8TQN6, A0A8V8TR70

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in interneurons differentiation. Involved in neuronal development and in neuromuscular junction formation.

Subcellular location. Cytoplasm. Nucleus. Postsynaptic cell membrane.

Tissue specificity. Expressed in fetal tissues, including in brain, intestine, lung, kidney and muscle. Isoform 1 is expressed in numerous fetal brain regions. Isoform 3 is highly expressed in numerous fetal brain regions and spinal cord.

Disease relevance. Wieacker-Wolf syndrome (WRWF) [MIM:314580] A severe X-linked recessive neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero (fetal akinesia). Affected boys are born with severe contractures, known as arthrogryposis, and have delayed motor development, facial and bulbar weakness, characteristic dysmorphic facial features, and skeletal abnormalities, such as hip dislocation, scoliosis, and pes equinovarus. Those that survive infancy show intellectual disability. Carrier females may have mild features of the disorder. The disease is caused by variants affecting the gene represented in this entry. Wieacker-Wolff syndrome, female-restricted (WRWFFR) [MIM:301041] An X-linked dominant neurodevelopmental disorder affecting the central and peripheral nervous systems. It is characterized by onset of muscle weakness in utero resulting in fetal akinesia, arthrogryposis multiplex congenita and diffuse contractures apparent at birth, global developmental delay with difficulty walking or inability to walk, hypotonia, variably impaired intellectual development, poor or absent speech and language, and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NQZ6-1	1	yes
Q9NQZ6-2	2
Q9NQZ6-3	3
Q9NQZ6-4	4
Q9NQZ6-5	5

RefSeq proteins (4): NP_001171503, NP_001171504, NP_001230733, NP_061154* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR018482	Znf-C4H2	Family
IPR044069	ZF_C4H2	Domain

Pfam: PF10146

UniProt features (27 total): sequence variant 16, splice variant 5, sequence conflict 3, chain 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9P3Z	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQZ6-F1	83.37	0.53

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 324 (showing top): GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, RRAGTTGT_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_NEUROGENESIS, GOBP_CELL_DIFFERENTIATION_IN_SPINAL_CORD, EFC_Q6, GOBP_SPINAL_CORD_MOTOR_NEURON_DIFFERENTIATION, GOBP_VENTRAL_SPINAL_CORD_DEVELOPMENT, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_CENTRAL_NERVOUS_SYSTEM_NEURON_DIFFERENTIATION, GOBP_PROTEIN_MONOUBIQUITINATION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION

GO Biological Process (9): noradrenergic neuron development (GO:0003358), protein monoubiquitination (GO:0006513), nervous system development (GO:0007399), neuromuscular junction development (GO:0007528), spinal cord motor neuron differentiation (GO:0021522), positive regulation of neuron differentiation (GO:0045666), obsolete positive regulation of DNA-binding transcription factor activity (GO:0051091), regulation of transcription regulatory region DNA binding (GO:2000677), cell differentiation (GO:0030154)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), protein-containing complex (GO:0032991), neuronal cell body (GO:0043025), postsynaptic membrane (GO:0045211), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
noradrenergic neuron differentiation	1
neuron development	1
protein ubiquitination	1
system development	1
synapse organization	1
cell differentiation in spinal cord	1
ventral spinal cord development	1
central nervous system neuron differentiation	1
neuron differentiation	1
positive regulation of cell differentiation	1
regulation of neuron differentiation	1
transcription cis-regulatory region binding	1
regulation of DNA binding	1
cellular developmental process	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular_component	1
somatodendritic compartment	1
cell body	1
synaptic membrane	1
postsynapse	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZC4H2	RNF220	Q5VTB9	742
ZC4H2	LAS1L	Q9Y4W2	477
ZC4H2	NEXMIF	Q5QGS0	466
ZC4H2	NALF2	O75949	466
ZC4H2	IGHMBP2	P38935	458
ZC4H2	TMEM132E	Q6IEE7	443
ZC4H2	OPHN1	O60890	439
ZC4H2	ZNF707	Q96C28	436
ZC4H2	MFSD12	Q6NUT3	429
ZC4H2	ZDHHC9	Q9Y397	413
ZC4H2	SLC9A6	Q92581	412
ZC4H2	ZNF182	P17025	411
ZC4H2	ECEL1	O95672	410
ZC4H2	RAB39B	Q96DA2	400
ZC4H2	KLHL40	Q2TBA0	399

IntAct

85 interactions, top by confidence:

A	B	Type	Score
ZNF490	ZC4H2	psi-mi:“MI:0915”(physical association)	0.780
ZC4H2	ZNF490	psi-mi:“MI:0915”(physical association)	0.780
HMG20A	KDM1A	psi-mi:“MI:0914”(association)	0.730
ZNF250	ZC4H2	psi-mi:“MI:0915”(physical association)	0.720
ZC4H2	ZNF250	psi-mi:“MI:0915”(physical association)	0.720
ZNF223	ZC4H2	psi-mi:“MI:0915”(physical association)	0.670
ZC4H2	ZNF223	psi-mi:“MI:0915”(physical association)	0.670
ZC4H2	KXD1	psi-mi:“MI:0915”(physical association)	0.660
ZC4H2	SORBS3	psi-mi:“MI:0915”(physical association)	0.560
ZNF524	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560
ZNF688	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560
FAM161B	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560
PRPH	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560
PLEKHN1	ZC4H2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (61): ZC4H2 (Two-hybrid), ZC4H2 (Two-hybrid), ZNF490 (Two-hybrid), ZNF250 (Two-hybrid), ZNF524 (Two-hybrid), AGGF1 (Affinity Capture-MS), HOOK3 (Affinity Capture-MS), RNF220 (Affinity Capture-MS), KXD1 (Two-hybrid), ZNF250 (Two-hybrid), ZC4H2 (Affinity Capture-MS), AGGF1 (Affinity Capture-MS), RNF220 (Affinity Capture-MS), ZC4H2 (Affinity Capture-MS), ZC4H2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2P884, A2AL36, A2CE83, O08970, P12757, P27628, P39880, P53564, P53565, P57077, P58500, Q13625, Q15025, Q155Q3, Q2KJE0, Q2VUH7, Q3T0L1, Q3UH68, Q3UKC1, Q53HC0, Q5R431, Q5R4C9, Q5R4U3, Q5SZL2, Q5XHZ2, Q60665, Q66HA4, Q68FG0, Q6AYB8, Q6P132, Q6P3P1, Q7T3I0, Q80Y83, Q86VP1, Q8BGI4, Q8C115, Q8CG79, Q8HYW0, Q8IVE3, Q8K342

Diamond homologs: Q68FG0, Q7T3I0, Q9NQZ6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

267 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	31
Uncertain significance	93
Likely benign	43
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1059458	NM_018684.4(ZC4H2):c.627G>C (p.Lys209Asn)	Pathogenic
1164068	NM_018684.4(ZC4H2):c.575G>A (p.Cys192Tyr)	Pathogenic
1691750	NM_018684.4(ZC4H2):c.450del (p.Ile151fs)	Pathogenic
1698141	NM_018684.4(ZC4H2):c.2T>C (p.Met1Thr)	Pathogenic
1804075	NM_018684.4(ZC4H2):c.172G>T (p.Glu58Ter)	Pathogenic
208658	NM_018684.4(ZC4H2):c.148C>T (p.Gln50Ter)	Pathogenic
2426481	NC_000023.10:g.(?64196185)(64196257_?)del	Pathogenic
2582376	NM_018684.4(ZC4H2):c.388del (p.Leu130fs)	Pathogenic
3192475	NM_018684.4(ZC4H2):c.362del (p.Pro121fs)	Pathogenic
3342864	NM_018684.4(ZC4H2):c.487C>T (p.Gln163Ter)	Pathogenic
3764193	NM_018684.4(ZC4H2):c.53+1G>A	Pathogenic
378042	NM_018684.4(ZC4H2):c.197T>A (p.Leu66His)	Pathogenic
378045	NM_018684.4(ZC4H2):c.53G>A (p.Arg18Lys)	Pathogenic
3899329	NM_018684.4(ZC4H2):c.442G>T (p.Glu148Ter)	Pathogenic
4056437	NM_018684.4(ZC4H2):c.225+1G>T	Pathogenic
422280	NM_018684.4(ZC4H2):c.200G>A (p.Arg67Gln)	Pathogenic
427151	NM_018684.4(ZC4H2):c.225+5G>C	Pathogenic
488641	NM_018684.4(ZC4H2):c.22_23del (p.Met8fs)	Pathogenic
50980	NM_018684.4(ZC4H2):c.187G>C (p.Val63Leu)	Pathogenic
50983	NM_018684.4(ZC4H2):c.637C>T (p.Arg213Trp)	Pathogenic
520928	NM_018684.4(ZC4H2):c.450dup (p.Ile151fs)	Pathogenic
598761	Single allele	Pathogenic
689619	NM_018684.4(ZC4H2):c.412C>T (p.Gln138Ter)	Pathogenic
817348	NM_018684.4(ZC4H2):c.125_129dup (p.His44fs)	Pathogenic
834094	NM_018684.4(ZC4H2):c.225+2T>C	Pathogenic
834096	NM_018684.4(ZC4H2):c.275_276del (p.Glu92fs)	Pathogenic
834097	NM_018684.4(ZC4H2):c.650A>G (p.Lys217Arg)	Pathogenic
834098	NC_000023.10:g.(?64166588)(64361318_?)del	Pathogenic
834099	NM_018684.4(ZC4H2):c.426G>A (p.Trp142Ter)	Pathogenic
834100	NM_018684.4(ZC4H2):c.67C>T (p.Gln23Ter)	Pathogenic

SpliceAI

583 predictions. Top by Δscore:

Variant	Effect	Δscore
X:64917892:CAGGC:C	acceptor_gain	1.0000
X:64917894:GGC:G	acceptor_gain	1.0000
X:64917895:GC:G	acceptor_gain	1.0000
X:64917895:GCCTG:G	acceptor_loss	1.0000
X:64917896:CC:C	acceptor_gain	1.0000
X:64919205:C:CC	acceptor_gain	1.0000
X:64919207:T:C	acceptor_gain	1.0000
X:64920075:G:C	donor_gain	1.0000
X:64920075:GCTTA:G	donor_loss	1.0000
X:64920076:CTTAC:C	donor_loss	1.0000
X:64920077:TTAC:T	donor_loss	1.0000
X:64920078:TA:T	donor_loss	1.0000
X:64920079:A:AC	donor_gain	1.0000
X:64920079:ACT:A	donor_gain	1.0000
X:64920079:ACTC:A	donor_gain	1.0000
X:64920080:C:CC	donor_gain	1.0000
X:64920080:CT:C	donor_gain	1.0000
X:64920080:CTC:C	donor_gain	1.0000
X:64920080:CTCC:C	donor_gain	1.0000
X:64920080:CTCCA:C	donor_gain	1.0000
X:64920082:C:CA	donor_gain	1.0000
X:64920260:C:CT	acceptor_gain	1.0000
X:64920261:A:C	acceptor_gain	1.0000
X:64921812:CGTA:C	donor_loss	1.0000
X:64921813:GTA:G	donor_loss	1.0000
X:64921814:TA:T	donor_loss	1.0000
X:64921815:A:AC	donor_gain	1.0000
X:64921815:AC:A	donor_gain	1.0000
X:64921816:C:CC	donor_gain	1.0000
X:64921816:CC:C	donor_gain	1.0000

AlphaMissense

1489 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:64917809:T:C	K217E	1.000
X:64917810:T:A	K216N	1.000
X:64917810:T:G	K216N	1.000
X:64917811:T:A	K216I	1.000
X:64917812:T:C	K216E	1.000
X:64917814:G:T	P215H	1.000
X:64917815:G:A	P215S	1.000
X:64917818:T:C	N214D	1.000
X:64917821:G:A	R213W	1.000
X:64917823:G:A	S212F	1.000
X:64917823:G:C	S212C	1.000
X:64917826:C:T	R211Q	1.000
X:64917827:G:A	R211W	1.000
X:64917827:G:C	R211G	1.000
X:64917828:A:C	S210R	1.000
X:64917828:A:T	S210R	1.000
X:64917829:C:A	S210I	1.000
X:64917830:T:G	S210R	1.000
X:64917831:C:A	K209N	1.000
X:64917831:C:G	K209N	1.000
X:64917832:T:A	K209M	1.000
X:64917833:T:C	K209E	1.000
X:64917833:T:G	K209Q	1.000
X:64917835:G:T	A208D	1.000
X:64917836:C:G	A208P	1.000
X:64917837:C:A	K207N	1.000
X:64917837:C:G	K207N	1.000
X:64917838:T:A	K207M	1.000
X:64917838:T:G	K207T	1.000
X:64917839:T:C	K207E	1.000

dbSNP variants (sampled 300 via entrez): RS1000021906 (X:64927352 A>G), RS1000031975 (X:65035398 C>G), RS1000041241 (X:64974633 C>T), RS1000058155 (X:65032059 T>C), RS1000069040 (X:64965088 A>G), RS1000084174 (X:65035809 A>G), RS1000117588 (X:64990426 G>T), RS1000120617 (X:64961329 C>G), RS1000128091 (X:64955328 AG>A), RS1000131825 (X:64919267 A>C,G), RS1000136503 (X:64965703 T>C), RS1000206742 (X:64976432 G>A), RS1000223651 (X:64944125 A>C,G), RS1000286378 (X:64999046 T>A,G), RS1000292495 (X:64919605 G>A)

Disease associations

OMIM: gene MIM:300897 | disease phenotypes: MIM:301041, MIM:314580, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
Wieacker-Wolff syndrome, female-restricted	Definitive	X-linked
Wieacker-Wolff syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Definitive	XL

Mondo (5): Wieacker-Wolff syndrome, female-restricted (MONDO:0026762), Wieacker-Wolff syndrome (MONDO:0010758), Wieacker-Wolff syndrome (spectrum) (MONDO:0025445), neurodevelopmental disorder (MONDO:0700092), genetic developmental and epileptic encephalopathy (MONDO:0100062)

Orphanet (2): Wieacker-Wolff syndrome (Orphanet:3454), X-linked intellectual disability, Miles-Carpenter type (Orphanet:85283)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000020	Urinary incontinence
HP:0000175	Cleft palate
HP:0000187	Broad alveolar ridges
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000496	Abnormality of eye movement
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000577	Exotropia
HP:0000582	Upslanted palpebral fissure
HP:0000657	Oculomotor apraxia
HP:0000750	Delayed speech and language development
HP:0000774	Narrow chest
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000824_11	Erectile dysfunction and prostate cancer treatment	7.000000e-07
GCST006661_29	Male-pattern baldness	4.000000e-13

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625
C536703	Wieacker syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	increases expression, affects expression	2
Cadmium Chloride	decreases expression, increases abundance	2
nickel sulfate	decreases expression	1
entinostat	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vanadates	decreases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

5 cell lines: 2 transformed cell line, 2 finite cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C7MA	GM28362	Transformed cell line	Female
CVCL_C7MB	GM28363	Finite cell line	Female
CVCL_C7MC	GM28603	Induced pluripotent stem cell	Female
CVCL_D6XT	GM28550	Transformed cell line	Female
CVCL_D6XU	GM28551	Finite cell line	Female

Clinical trials (associated diseases)

214 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase