CDH4

Summary

CDH4 (cadherin 4, HGNC:1763) is a protein-coding gene on chromosome 20q13.33, encoding Cadherin-4 (P55283). Cadherins are calcium-dependent cell adhesion proteins.

This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 1002 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies/dysmorphic syndrome (Limited, GenCC)
• GWAS associations: 34
• Clinical variants (ClinVar): 208 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_001794

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1763
Approved symbol	CDH4
Name	cadherin 4
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	R-CAD
Ensembl gene	ENSG00000179242
Ensembl biotype	protein_coding
OMIM	603006
Entrez	1002

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000543233, ENST00000611855, ENST00000614565

RefSeq mRNA: 3 — MANE Select: NM_001794 NM_001252338, NM_001252339, NM_001794

CCDS: CCDS13488, CCDS58784

Canonical transcript exons

ENST00000614565 — 16 exons

Exon	Start	End
ENSE00000897114	61924334	61924476
ENSE00000897130	61932985	61933124
ENSE00001042361	61773003	61773182
ENSE00001109129	61928190	61928423
ENSE00001109136	61844668	61844823
ENSE00001237595	61934056	61934220
ENSE00001237608	61929609	61929842
ENSE00001237619	61923451	61923704
ENSE00001237625	61910422	61910607
ENSE00001237632	61873728	61873900
ENSE00001237637	61852754	61852898
ENSE00001773338	61894910	61895047
ENSE00003712410	61743563	61743789
ENSE00003718800	61936737	61940617
ENSE00003727525	61254826	61254937
ENSE00003740340	61252261	61252570

Expression profiles

Bgee: expression breadth ubiquitous, 118 present calls, max score 92.40.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7783 / max 117.4642, expressed in 795 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185687	3.6126	794
185692	0.0777	37
185691	0.0571	30
185690	0.0310	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	92.40	gold quality
ganglionic eminence	UBERON:0004023	89.39	gold quality
adrenal tissue	UBERON:0018303	83.61	gold quality
nucleus accumbens	UBERON:0001882	81.98	gold quality
temporal lobe	UBERON:0001871	81.86	gold quality
amygdala	UBERON:0001876	81.76	gold quality
caudate nucleus	UBERON:0001873	80.25	gold quality
anterior cingulate cortex	UBERON:0009835	78.93	gold quality
putamen	UBERON:0001874	78.59	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.56	gold quality
cortical plate	UBERON:0005343	78.52	gold quality
prefrontal cortex	UBERON:0000451	78.20	gold quality
frontal cortex	UBERON:0001870	77.94	gold quality
cerebral cortex	UBERON:0000956	77.70	gold quality
right frontal lobe	UBERON:0002810	77.53	gold quality
superior frontal gyrus	UBERON:0002661	77.48	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	77.38	gold quality
stromal cell of endometrium	CL:0002255	76.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	76.44	gold quality
Ammon’s horn	UBERON:0001954	75.98	gold quality
left ovary	UBERON:0002119	73.65	gold quality
primary visual cortex	UBERON:0002436	73.41	gold quality
hypothalamus	UBERON:0001898	73.09	gold quality
brain	UBERON:0000955	72.43	gold quality
ovary	UBERON:0000992	71.95	gold quality
right ovary	UBERON:0002118	69.56	gold quality
spleen	UBERON:0002106	68.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.94	gold quality
substantia nigra	UBERON:0002038	67.23	gold quality
hindlimb stylopod muscle	UBERON:0004252	63.87	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6, STAT3

miRNA regulators (miRDB)

101 targeting CDH4, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-3919	99.87	69.45	2489
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466

Literature-anchored findings (GeneRIF, showing 21)

• R-cadherin induces cell motility when expressed in epithelial cells, and this increased motility is dependent upon Rho GTPase activity. (PMID:15143071)
• CDH4 may act as a tumor suppressor gene in human gastrointestinal tumors and can potentially be used as an early diagnostic marker for gastrointestinal tumorigenesis (PMID:15548679)
• the degradation of E-cadherin in response to expression of R-cadherin is due to competition for p120(ctn) (PMID:16786001)
• a novel putative tumor suppressor gene that can be frequently and tumor-specifically inactivated by its promoter methylation in nasopharyngeal carcinoma (PMID:21665361)
• Findings identify an important role of CHD4 in controlling homologous recombination repair to maintain genome stability and establish the potential therapeutic implications of targeting CHD4 deficiency in tumors. (PMID:22219182)
• R-cadherin adherens junction formation facilitates a mesenchymal to epithelial-like transition in MDA-MB-231 cells. (PMID:22820501)
• P-cadherin expression correlated with tumor progression and could be an independent predictor for bladder cancer survival. (PMID:24429027)
• Data show that low expression of R-cadherin is associated with the poor prognosis in gastric cancer. (PMID:27029387)
• Further knockdown R-cadherin in linc-cdh4-2 stably overexpressed cells, could significantly upregulate the protein levels of RAC1 and improve the cell migration and invasion abilities. Taken together, the novel linc-cdh4-2 may negatively regulate the motility of the HCC cells through targeting R-cadherin-RAC1 signaling pathway. (PMID:27765630)
• CDH4 may play a negative role in the growth and metastasis of salivary adenoid cystic carcinoma via co-expression with E-cadherin. (PMID:27783992)
• Low expression of CDH4 is associated with lung cancer. (PMID:28095912)
• CDH4 overexpression activates c-Jun via the JNK pathway, while CDH4 knockdown suppresses both tumor xenograft growth and lung colonization. (PMID:29610525)
• Cdh4 regulates cell proliferation, cell migration and tumorigenic potential of patient derived glioblastoma cells. (PMID:31426573)
• High CDH4 expression is associated with triple-negative breast cancer. (PMID:31639396)
• Expression and Prognostic Significance of Cadherin 4 (CDH4) in Renal Cell Carcinoma. (PMID:32511216)
• Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome. (PMID:32757270)
• Cadherin switches during epithelial-mesenchymal transition: CDH4/RCAD downregulation reduces bladder cancer progression. (PMID:35064910)
• Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity. (PMID:36362280)
• CDH4 inhibits ferroptosis in oral squamous cell carcinoma cells. (PMID:37237299)
• Understanding the Role of CDH4 in Multiple System Atrophy Brain. (PMID:38143373)
• Cytosolic Cadherin 4 promotes angiogenesis and metastasis in papillary thyroid cancer by suppressing the ubiquitination/degradation of beta-catenin. (PMID:38402159)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdh4	ENSDARG00000015002
mus_musculus	Cdh4	ENSMUSG00000000305
rattus_norvegicus	Cdh4	ENSRNOG00000052405

Paralogs (33): CDH1 (ENSG00000039068), CDH10 (ENSG00000040731), CDH3 (ENSG00000062038), CDH19 (ENSG00000071991), CDHR2 (ENSG00000074276), CDH17 (ENSG00000079112), CDH7 (ENSG00000081138), PCDH11Y (ENSG00000099715), CDHR5 (ENSG00000099834), CDH20 (ENSG00000101542), PCDH11X (ENSG00000102290), CDH23 (ENSG00000107736), CDH9 (ENSG00000113100), CDH6 (ENSG00000113361), CDH26 (ENSG00000124215), CDHR3 (ENSG00000128536), CDH15 (ENSG00000129910), CDH24 (ENSG00000139880), CDH11 (ENSG00000140937), CDH13 (ENSG00000140945), CDH18 (ENSG00000145526), CDHR1 (ENSG00000148600), CDH22 (ENSG00000149654), CDH8 (ENSG00000150394), CDH12 (ENSG00000154162), PCDH1 (ENSG00000156453), DCHS1 (ENSG00000166341), PCDH7 (ENSG00000169851), CDH2 (ENSG00000170558), CDH5 (ENSG00000179776), PCDH9 (ENSG00000184226), DCHS2 (ENSG00000197410), PCDH20 (ENSG00000280165)

Protein

Protein identifiers

Cadherin-4 — P55283 (reviewed: P55283)

Alternative names: Retinal cadherin

All UniProt accessions (2): A0A087WX99, P55283

UniProt curated annotations — full annotation on UniProt →

Function. Cadherins are calcium-dependent cell adhesion proteins. They preferentially interact with themselves in a homophilic manner in connecting cells; cadherins may thus contribute to the sorting of heterogeneous cell types. May play an important role in retinal development.

Subcellular location. Cell membrane.

Tissue specificity. Expressed mainly in brain but also found in other tissues.

Domain organisation. Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.

Isoforms (2)

UniProt ID	Names	Canonical?
P55283-1	1	yes
P55283-2	2

RefSeq proteins (3): NP_001239267, NP_001239268, NP_001785* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000233	Cadherin_Y-type_LIR	Domain
IPR002126	Cadherin-like_dom	Domain
IPR014868	Cadherin_pro_dom	Domain
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR039808	Cadherin	Family

Pfam: PF00028, PF01049, PF08758

UniProt features (37 total): sequence conflict 14, glycosylation site 6, domain 5, region of interest 2, sequence variant 2, topological domain 2, signal peptide 1, propeptide 1, compositionally biased region 1, chain 1, splice variant 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55283-F1	79.02	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (6): 283, 412, 557, 632, 661, 702

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-418990	Adherens junctions interactions
R-HSA-525793	Myogenesis
R-HSA-1266738	Developmental Biology
R-HSA-1500931	Cell-Cell communication
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization

MSigDB gene sets: 206 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_NEURON_PROJECTION_EXTENSION, MODULE_255, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_GROWTH, MODULE_317, SCHLESINGER_METHYLATED_DE_NOVO_IN_CANCER, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, MORF_RAD51L3, GOBP_CALCIUM_DEPENDENT_CELL_CELL_ADHESION, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, MODULE_66

GO Biological Process (13): cell morphogenesis (GO:0000902), cell-cell junction assembly (GO:0007043), cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156), heterophilic cell-cell adhesion (GO:0007157), axon guidance (GO:0007411), calcium-dependent cell-cell adhesion (GO:0016339), cell migration (GO:0016477), adherens junction organization (GO:0034332), cell-cell adhesion mediated by cadherin (GO:0044331), positive regulation of axon extension (GO:0045773), axon extension (GO:0048675), cell-cell adhesion (GO:0098609)

GO Molecular Function (4): calcium ion binding (GO:0005509), beta-catenin binding (GO:0008013), cadherin binding (GO:0045296), metal ion binding (GO:0046872)

GO Cellular Component (4): plasma membrane (GO:0005886), adherens junction (GO:0005912), catenin complex (GO:0016342), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Cell-cell junction organization	1
Developmental Biology	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	4
cell-cell junction organization	2
axonogenesis	2
anatomical structure morphogenesis	1
cell junction assembly	1
cellular process	1
neuron projection guidance	1
cell motility	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
neuron projection extension	1
cell adhesion	1
metal ion binding	1
protein binding	1
cell adhesion molecule binding	1
cation binding	1
membrane	1
cell periphery	1
cell-cell junction	1
extrinsic component of plasma membrane	1
plasma membrane protein complex	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1222 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDH4	KLRG1	Q96E93	805
CDH4	BRCA1	P38398	712
CDH4	TP53BP1	Q12888	679
CDH4	CTNNA1	P35221	554
CDH4	CDH19	Q9H159	519
CDH4	CDH20	Q9HBT6	507
CDH4	CDH7	Q9ULB5	502
CDH4	VCL	P18206	490
CDH4	CDH8	P55286	490
CDH4	SDK2	Q58EX2	474
CDH4	NRXN2	Q9P2S2	467
CDH4	LIMA1	Q9UHB6	461
CDH4	OLFM3	Q96PB7	459
CDH4	LAMA5	O15230	456
CDH4	CNTNAP2	Q9UHC6	452

IntAct

12 interactions, top by confidence:

A	B	Type	Score
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
Dlg4	CDH4	psi-mi:“MI:0407”(direct interaction)	0.440
CTNNA3	ARVCF	psi-mi:“MI:0914”(association)	0.350
CTNNB1	IGLL5	psi-mi:“MI:0914”(association)	0.350
PCDHGA6	TGFB1I1	psi-mi:“MI:0914”(association)	0.350
SRPRB	GSDME	psi-mi:“MI:0914”(association)	0.350
CDH4	MTNR1B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): CDH4 (Affinity Capture-MS), CDH4 (Biochemical Activity), CDH4 (Affinity Capture-MS), CDH4 (Two-hybrid), CDH4 (Affinity Capture-RNA), CDH2 (Affinity Capture-Western), CDH4 (Affinity Capture-RNA), CDH4 (Affinity Capture-MS), CDH4 (Affinity Capture-MS), CDH4 (Positive Genetic), CDH4 (Cross-Linking-MS (XL-MS)), CDH4 (Affinity Capture-MS), CDH4 (Affinity Capture-MS), CDH4 (Affinity Capture-MS), CDH4 (Affinity Capture-Western)

ESM2 similar proteins: A4IGL7, D3ZB51, E9PZ19, O75882, O94779, O95970, P00533, P02469, P07942, P13590, P15209, P24503, P24786, P33150, P39038, P55245, P55283, P68500, P97300, P97527, P97546, Q01279, Q01973, Q03351, Q16288, Q16620, Q1EGL2, Q3B7N0, Q3UQ28, Q5IFJ9, Q5IS37, Q5IS82, Q5R945, Q63604, Q6IS24, Q6VNS1, Q7TPD3, Q7TT15, Q8K4Y5, Q8N475

Diamond homologs: A0A8M2BIB6, B0KW95, B2KI42, B4USZ0, F1PAA9, H2EQR6, O18926, O35902, O55075, O55111, O88277, P08641, P09803, P10287, P10288, P12830, P15116, P19022, P19534, P19535, P20310, P22223, P24503, P30944, P32926, P33145, P33146, P33147, P33148, P33150, P33152, P33545, P39038, P55283, P55290, P55291, P55292, P55849, P55850, P79883

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
DIAPH1	“up-regulates activity”	CDH4
PFN1	“up-regulates activity”	CDH4
calcium(2+)	“up-regulates activity”	CDH4	“chemical activation”
CDH4	“up-regulates activity”	CTNNB1	binding
CDH4	“up-regulates activity”	RAC1
CDH4	“down-regulates quantity by repression”	CDH15
CDH4	“down-regulates quantity by repression”	CDH2

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	156
Likely benign	22
Benign	10

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
816131	GRCh37/hg19 20q13.31-13.33(chr20:55743522-62032989)x3	Pathogenic
402151	NM_001794.5(CDH4):c.1976G>C (p.Arg659Pro)	Likely pathogenic

SpliceAI

5433 predictions. Top by Δscore:

Variant	Effect	Δscore
20:61252569:GG:G	donor_gain	1.0000
20:61252570:GG:G	donor_gain	1.0000
20:61252571:G:GA	donor_loss	1.0000
20:61252571:G:GG	donor_gain	1.0000
20:61252572:T:G	donor_loss	1.0000
20:61254933:TCAAG:T	donor_loss	1.0000
20:61254934:CAAGG:C	donor_loss	1.0000
20:61254935:AAGG:A	donor_loss	1.0000
20:61254936:AGGT:A	donor_loss	1.0000
20:61254937:GGT:G	donor_loss	1.0000
20:61254938:G:C	donor_loss	1.0000
20:61254939:T:A	donor_loss	1.0000
20:61501946:G:GG	donor_gain	1.0000
20:61743560:CA:C	acceptor_loss	1.0000
20:61743561:A:AC	acceptor_loss	1.0000
20:61743561:A:AG	acceptor_gain	1.0000
20:61743562:G:GT	acceptor_gain	1.0000
20:61743562:GTC:G	acceptor_gain	1.0000
20:61743562:GTCA:G	acceptor_gain	1.0000
20:61743562:GTCAA:G	acceptor_gain	1.0000
20:61743788:AGGT:A	donor_loss	1.0000
20:61743789:GGTAA:G	donor_loss	1.0000
20:61743790:G:GA	donor_loss	1.0000
20:61743791:T:G	donor_loss	1.0000
20:61252566:TCCGG:T	donor_gain	0.9900
20:61252567:CCGG:C	donor_gain	0.9900
20:61252568:CGG:C	donor_gain	0.9900
20:61252569:GGG:G	donor_gain	0.9900
20:61254820:TCTCA:T	acceptor_loss	0.9900
20:61254821:CTCA:C	acceptor_loss	0.9900

AlphaMissense

6038 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:61773117:T:A	W171R	1.000
20:61773117:T:C	W171R	1.000
20:61773119:G:C	W171C	1.000
20:61773119:G:T	W171C	1.000
20:61852834:T:A	N271K	1.000
20:61852834:T:G	N271K	1.000
20:61852836:A:C	D272A	1.000
20:61852845:C:A	P275H	1.000
20:61873842:T:C	F331S	1.000
20:61773145:A:T	E180V	0.999
20:61773146:G:C	E180D	0.999
20:61773146:G:T	E180D	0.999
20:61844669:T:C	I193T	0.999
20:61844704:T:C	Y205H	0.999
20:61844704:T:G	Y205D	0.999
20:61844750:T:C	F220S	0.999
20:61844771:G:A	G227D	0.999
20:61844771:G:T	G227V	0.999
20:61844801:G:C	R237P	0.999
20:61852755:T:C	L245P	0.999
20:61852761:C:A	A247D	0.999
20:61852767:C:A	A249D	0.999
20:61852809:T:C	L263P	0.999
20:61852821:T:A	V267D	0.999
20:61852826:G:C	D269H	0.999
20:61852827:A:T	D269V	0.999
20:61852833:A:T	N271I	0.999
20:61852835:G:C	D272H	0.999
20:61852836:A:T	D272V	0.999
20:61852844:C:T	P275S	0.999

dbSNP variants (sampled 300 via entrez): RS1000000578 (20:61383820 C>A,T), RS1000001216 (20:61401206 A>T), RS1000003584 (20:61643429 G>A,T), RS1000005634 (20:61264238 G>A), RS1000010599 (20:61338291 GA>G,GAA), RS1000016609 (20:61650451 T>C), RS1000019042 (20:61611626 C>T), RS1000019371 (20:61669108 T>C), RS1000022995 (20:61545680 G>T), RS1000023855 (20:61500968 T>A), RS1000029691 (20:61531853 G>A), RS1000030360 (20:61803471 T>A), RS1000030807 (20:61699733 C>T), RS1000033325 (20:61526518 C>T), RS1000037101 (20:61579474 G>T)

Disease associations

OMIM: gene MIM:603006 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies/dysmorphic syndrome	Limited	Autosomal recessive

Mondo (2): neurodevelopmental disorder (MONDO:0700092), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

34 associations (top):

Study	Trait	p-value
GCST000088_3	Volumetric brain MRI	4.000000e-08
GCST000785_9	Longevity	1.000000e-06
GCST000826_1	Cerebrospinal T-tau levels	6.000000e-07
GCST001102_5	Sudden cardiac arrest	2.000000e-06
GCST001762_41	Obesity-related traits	4.000000e-06
GCST001762_468	Obesity-related traits	1.000000e-07
GCST001762_87	Obesity-related traits	7.000000e-06
GCST001800_7	β2-Glycoprotein I (β2-GPI) plasma levels	2.000000e-06
GCST002115_21	Axial length	3.000000e-06
GCST002119_9	Metabolite levels (X-11787)	8.000000e-06
GCST003075_31	Cognitive decline rate in late mild cognitive impairment	7.000000e-07
GCST003542_199	Night sleep phenotypes	9.000000e-06
GCST003675_6	Obstructive sleep apnea trait (average respiratory event duration)	1.000000e-07
GCST003784_22	Multiple system atrophy	4.000000e-06
GCST005173_5	Coronary artery calcified atherosclerotic plaque (130 HU threshold) in type 2 diabetes	4.000000e-06
GCST006218_108	Erosive tooth wear (severe vs non-severe)	9.000000e-06
GCST006218_25	Erosive tooth wear (severe vs non-severe)	1.000000e-07
GCST006218_51	Erosive tooth wear (severe vs non-severe)	1.000000e-07
GCST006218_52	Erosive tooth wear (severe vs non-severe)	3.000000e-08
GCST006226_9	Erosive tooth wear (severe vs none or mild)	5.000000e-06
GCST006269_1208	General cognitive ability	4.000000e-08
GCST006269_1214	General cognitive ability	4.000000e-08
GCST007673_19	3-month functional outcome in ischaemic stroke (modified Rankin score)	2.000000e-06
GCST008156_91	Hip circumference adjusted for BMI	6.000000e-06
GCST008597_4	Fish intake frequency	5.000000e-07
GCST009391_1004	Metabolite levels	1.000000e-06
GCST009391_1013	Metabolite levels	5.000000e-07
GCST009391_2022	Metabolite levels	9.000000e-07
GCST009524_182	Household income (MTAG)	1.000000e-08
GCST009524_6	Household income (MTAG)	2.000000e-10

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0004868	volumetric brain MRI
EFO:0004760	t-tau measurement
EFO:0004278	sudden cardiac arrest
EFO:0004626	IGFBP-3 measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004555	glycoprotein measurement
EFO:0005318	axial length measurement
EFO:0005276	hydroxy-leucine measurement
EFO:0007710	cognitive decline measurement
EFO:0007817	sleep apnea measurement
EFO:0004723	coronary artery calcification
EFO:0004337	intelligence
EFO:0009603	stroke outcome severity measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0010139	fish consumption measurement
EFO:0010359	lysophosphatidylcholine 18:0 measurement
EFO:0010360	lysophosphatidylcholine 18:1 measurement
EFO:0010371	lysophosphatidylethanolamine 22:6 measurement
EFO:0009695	household income
EFO:0007874	gut microbiome measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4925300	CDH4		0.00	0
rs4925193	CDH4		0.00	0

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation, decreases expression	5
Acetaminophen	decreases expression	2
Arsenic	affects methylation, decreases methylation, increases abundance	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Silicon Dioxide	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, increases methylation	2
aristolochic acid I	increases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases methylation	1
trichostatin A	decreases expression	1
methylparaben	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	increases methylation	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
jinfukang	decreases expression, increases reaction	1
Irinotecan	decreases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1

Clinical trials (associated diseases)

202 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
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
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
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
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice