Neural tube defect

disease

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Also known as NTDspinal dysraphism

Summary

Neural tube defect (MONDO:0018075) is a disease (an umbrella term covering 12 Mondo subtypes) caused by SHROOM3 (GenCC Strong), with 16 cohort genes and 12 clinical trials. The dominant Reactome pathway is RND3 GTPase cycle (3 cohort genes).

At a glance

Prevalence: 6-9 / 10 000 (Europe) [Orphanet-validated]
Causal gene: SHROOM3 (GenCC Strong)
Umbrella term: 12 Mondo subtypes
Cohort genes: 16
ClinVar variants: 211
Clinical trials: 12

Clinical features

Epidemiology

Prevalence records

23 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Prevalence at birth	6-9 / 10 000	91.05	Europe	Validated
Prevalence at birth	6-9 / 10 000	55	United States	Validated
Prevalence at birth	6-9 / 10 000	88.75	Belgium	Validated
Prevalence at birth	6-9 / 10 000	76.8	Austria	Validated
Prevalence at birth	6-9 / 10 000	74.7	Czech Republic	Validated
Prevalence at birth	1-5 / 10 000	47.9	Croatia	Validated
Prevalence at birth	>1 / 1000	109.6	Denmark	Validated
Prevalence at birth	6-9 / 10 000	86.7	Finland	Validated
Prevalence at birth	>1 / 1000	120.2	France	Validated
Prevalence at birth	>1 / 1000	138.25	Germany	Validated
Prevalence at birth	6-9 / 10 000	67.2	Hungary	Validated
Prevalence at birth	6-9 / 10 000	87.4	Ireland	Validated
Prevalence at birth	1-5 / 10 000	54.65	Italy	Validated
Prevalence at birth	>1 / 1000	109.5	Malta	Validated
Prevalence at birth	6-9 / 10 000	84.2	Netherlands	Validated
Prevalence at birth	6-9 / 10 000	92.7	Norway	Validated
Prevalence at birth	6-9 / 10 000	92.5	Poland	Validated
Prevalence at birth	1-5 / 10 000	47.3	Portugal	Validated
Prevalence at birth	6-9 / 10 000	98.5	Spain	Validated
Prevalence at birth	>1 / 1000	101.7	Switzerland	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neural tube defect
Mondo ID	MONDO:0018075
MeSH	D009436
Orphanet	3388
DOID	DOID:0080074
NCIT	C84923
SNOMED CT	253098009
UMLS	C0027794
MedGen	18009
GARD	0018796
Is cancer (heuristic)	no

Also known as: NTD · spinal dysraphism

Data availability: 211 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 12 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › neural tube defect

Subtypes (12): Chiari malformation type I, lateral meningocele syndrome, diastematomyelia, lipomyelomeningocele, sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome, leptomyelolipoma, primary tethered cord syndrome, neurenteric cyst, isolated amyelia, caudal regression sequence, parietal foramina, iniencephaly

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

211 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 35 benign/likely benign, 31 conflicting classifications of pathogenicity, 25 benign, 7 likely pathogenic, 6 risk factor, 5 pathogenic, 1 uncertain significance; association, 1 pathogenic; risk factor, 1 pathogenic/likely pathogenic, 1 affects

ClinVar	Variant (HGVS)	Gene	Classification	Review
560606	NM_017635.5(KMT5B):c.559C>T (p.Arg187Ter)	KMT5B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187898	NM_005957.5(MTHFR):c.1683G>A (p.Trp561Ter)	MTHFR	Pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
254185	NM_001184785.2(PARD3):c.2729C>A (p.Pro910Gln)	PARD3	Pathogenic	no assertion criteria provided
254187	NM_001184785.2(PARD3):c.2339A>G (p.Asp780Gly)	PARD3	Pathogenic	no assertion criteria provided
254190	NC_000010.10:g.34835589_34975192del139604	PARD3	Pathogenic	no assertion criteria provided
694400	NM_001286535.2(RAD9B):c.960del (p.Ala321fs)	RAD9B	Pathogenic	no assertion criteria provided
694421	NM_001286535.2(RAD9B):c.1199dup (p.Arg401fs)	RAD9B	Pathogenic	no assertion criteria provided
694312	NM_001286535.2(RAD9B):c.661G>A (p.Gly221Arg)	RAD9B	Likely pathogenic	no assertion criteria provided
694313	NC_000012.11:g.110950633C>G	RAD9B	Likely pathogenic	no assertion criteria provided
694314	NM_001286535.2(RAD9B):c.336A>G (p.Ile112Met)	RAD9B	Likely pathogenic	no assertion criteria provided
694315	NM_001286535.2(RAD9B):c.1060A>G (p.Ser354Gly)	RAD9B	Likely pathogenic	no assertion criteria provided
694398	NM_001286535.2(RAD9B):c.28A>G (p.Ser10Gly)	RAD9B	Likely pathogenic	no assertion criteria provided
694399	NM_001286535.2(RAD9B):c.645T>A (p.Phe215Leu)	RAD9B	Likely pathogenic	no assertion criteria provided
1077121	NM_182706.5(SCRIB):c.1177C>T (p.Gln393Ter)	SCRIB	Likely pathogenic	criteria provided, single submitter
518460	NM_182643.3(DLC1):c.1432C>T (p.Pro478Ser)	DLC1	risk factor	criteria provided, single submitter
518461	NM_182643.3(DLC1):c.2377C>T (p.Gln793Ter)	DLC1	risk factor	criteria provided, single submitter
518462	NM_002211.4(ITGB1):c.2303dup (p.Glu769fs)	ITGB1	risk factor	criteria provided, single submitter
254184	NM_001184785.2(PARD3):c.3736G>A (p.Gly1246Ser)	PARD3	risk factor	no assertion criteria provided
254186	NM_001184785.2(PARD3):c.2572A>T (p.Thr858Ser)	PARD3	risk factor	no assertion criteria provided
254189	NM_001184785.2(PARD3):c.583-3T>C	PARD3	risk factor	no assertion criteria provided
292001	NM_138959.3(VANGL1):c.-115G>C	LOC121725046	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
167818	NM_138959.3(VANGL1):c.523C>T (p.Arg175Trp)	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292003	NM_138959.3(VANGL1):c.114C>T (p.Asp38=)	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292006	NM_138959.3(VANGL1):c.572T>C (p.Val191Ala)	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292007	NM_138959.3(VANGL1):c.575T>C (p.Leu192Pro)	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292009	NM_138959.3(VANGL1):c.812+9C>T	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292013	NM_138959.3(VANGL1):c.1172G>T (p.Arg391Met)	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292033	NM_138959.3(VANGL1):c.*1043A>G	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292039	NM_138959.3(VANGL1):c.*1545A>G	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292051	NM_138959.3(VANGL1):c.*2336A>G	VANGL1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 12 · 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
SHROOM3	Strong	Autosomal dominant	neural tube defect	2
HECTD1	Limited	Autosomal dominant	neural tube defect	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBXT	Orphanet:178	Chordoma
TBXT	Orphanet:397927	Sacral agenesis-abnormal ossification of the vertebral bodies-persistent notochordal canal syndrome
VANGL2	Orphanet:563609	Isolated anencephaly
VANGL2	Orphanet:563612	Isolated exencephaly
VANGL1	Orphanet:3027	Caudal regression syndrome
ARSG	Orphanet:231183	Usher syndrome type 3
KMT5B	Orphanet:684226	Intellectual disability-hypotonia-facial dysmorphism-macrocephaly syndrome
FUZ	Orphanet:3027	Caudal regression syndrome
FUZ	Orphanet:620158	Non-syndromic non-specific multisutural craniosynostosis
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly

Cohort genes → proteins

16 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	16

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HECTD1	HGNC:20157	ENSG00000092148	Q9ULT8	E3 ubiquitin-protein ligase HECTD1	gencc
SHROOM3	HGNC:30422	ENSG00000138771	Q8TF72	Protein Shroom3	gencc
TBXT	HGNC:11515	ENSG00000164458	O15178	T-box transcription factor T	clinvar
VANGL2	HGNC:15511	ENSG00000162738	Q9ULK5	Vang-like protein 2	clinvar
VANGL1	HGNC:15512	ENSG00000173218	Q8TAA9	Vang-like protein 1	clinvar
PARD3	HGNC:16051	ENSG00000148498	Q8TEW0	Partitioning defective 3 homolog	clinvar
RAD9B	HGNC:21700	ENSG00000151164	Q6WBX8	Cell cycle checkpoint control protein RAD9B	clinvar
ARSG	HGNC:24102	ENSG00000141337	Q96EG1	Arylsulfatase G	clinvar
KMT5B	HGNC:24283	ENSG00000110066	Q4FZB7	Histone-lysine N-methyltransferase KMT5B	clinvar
AMBRA1	HGNC:25990	ENSG00000110497	Q9C0C7	Activating molecule in BECN1-regulated autophagy protein 1	clinvar
FUZ	HGNC:26219	ENSG00000010361	Q9BT04	Protein fuzzy homolog	clinvar
DLC1	HGNC:2897	ENSG00000164741	Q96QB1	Rho GTPase-activating protein 7	clinvar
SCRIB	HGNC:30377	ENSG00000180900	C0HLS1	SCRIB overlapping open reading frame protein	clinvar
APAF1	HGNC:576	ENSG00000120868	O14727	Apoptotic protease-activating factor 1	clinvar
ITGB1	HGNC:6153	ENSG00000150093	P05556	Integrin beta-1	clinvar
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HECTD1	E3 ubiquitin-protein ligase HECTD1	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.
SHROOM3	Protein Shroom3	Controls cell shape changes in the neuroepithelium during neural tube closure.
TBXT	T-box transcription factor T	Involved in the transcriptional regulation of genes required for mesoderm formation and differentiation.
VANGL2	Vang-like protein 2	Involved in the control of early morphogenesis and patterning of both axial midline structures and the development of neural plate.
PARD3	Partitioning defective 3 homolog	Adapter protein involved in asymmetrical cell division and cell polarization processes.
ARSG	Arylsulfatase G	Displays arylsulfatase activity at acidic pH towards artificial substrates, such as p-nitrocatechol sulfate and also, but with a lower activity towards p-nitrophenyl sulfate and 4-methylumbelliferyl sulfate.
KMT5B	Histone-lysine N-methyltransferase KMT5B	Histone methyltransferase that specifically methylates monomethylated ‘Lys-20’ (H4K20me1) and dimethylated ‘Lys-20’ (H4K20me2) of histone H4 to produce respectively dimethylated ‘Lys-20’ (H4K20me2) and trimethylated ‘Lys-20’ (H4K20me3) and…
AMBRA1	Activating molecule in BECN1-regulated autophagy protein 1	Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex involved in cell cycle control and autophagy.
FUZ	Protein fuzzy homolog	Probable planar cell polarity effector involved in cilium biogenesis.
DLC1	Rho GTPase-activating protein 7	Functions as a GTPase-activating protein for the small GTPases RHOA, RHOB, RHOC and CDC42, terminating their downstream signaling.
SCRIB	SCRIB overlapping open reading frame protein	Represses translation of the downstream SCRIB protein.
APAF1	Apoptotic protease-activating factor 1	Oligomeric Apaf-1 mediates the cytochrome c-dependent autocatalytic activation of pro-caspase-9 (Apaf-3), leading to the activation of caspase-3 and apoptosis.
ITGB1	Integrin beta-1	Integrins alpha-1/beta-1, alpha-2/beta-1, alpha-10/beta-1 and alpha-11/beta-1 are receptors for collagen.
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.

Protein-family classification

Druggable: 2 · Difficult: 7 · Unknown: 7 · Druggable fraction: 0.12

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
Scaffold/PPI	6	6.5×	9e-04
Phosphatase	1	5.2×	0.437
Other/Unknown	7	0.8×	0.889
Enzyme (other)	1	0.8×	0.889
Transcription factor	1	0.5×	0.889

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HECTD1	Scaffold/PPI	no		HECT_dom, Ankyrin_rpt, Galactose-bd-like_sf
SHROOM3	Scaffold/PPI	no		PDZ, ASD2_dom, ASD1_dom
TBXT	Transcription factor	no		TF_T-box, TF_Brachyury, p53-like_TF_DNA-bd_sf
VANGL2	Other/Unknown	no		VANGL
VANGL1	Other/Unknown	no		VANGL
PARD3	Scaffold/PPI	no		PDZ, Par3/HAL_N, PDZ_sf
RAD9B	Other/Unknown	no		Rad9/Ddc1, Rad9, DNA_clamp_sf
ARSG	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
KMT5B	Other/Unknown	no		SET_dom, Suv4-20_animal, Suv4-20/Set9
AMBRA1	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
FUZ	Other/Unknown	no		Fuzzy, FUZ/MON1/HPS1_longin_3, FUZ/MON1/HPS1_longin_2
DLC1	Other/Unknown	no		RhoGAP_dom, SAM, START_lipid-bd_dom
SCRIB	Scaffold/PPI	no		PDZ, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
APAF1	Scaffold/PPI	no		CARD, WD40_rpt, NB-ARC
ITGB1	Other/Unknown	no		Integrin_bsu_VWA, Integrin_bsu_tail, EGF_extracell
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like

Expression context

Cohort genes with no expression data: 0.

15 cohort genes 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)	16
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	2
pancreatic ductal cell	2
male germ line stem cell (sensu Vertebrata) in testis	2
primordial germ cell in gonad	2
corpus epididymis	2
cervix squamous epithelium	2
secondary oocyte	2
right testis	2
monocyte	2
visceral pleura	2
right uterine tube	2
sural nerve	2
deltoid	1
tibialis anterior	1
epithelial cell of pancreas	1
buccal mucosa cell	1
ganglionic eminence	1
ventricular zone	1
bronchial epithelial cell	1
caput epididymis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HECTD1	256	ubiquitous	marker	tibialis anterior, deltoid, ileal mucosa
SHROOM3	229	ubiquitous	marker	ileal mucosa, epithelial cell of pancreas, pancreatic ductal cell
TBXT	42	tissue_specific	marker	primordial germ cell in gonad, pancreatic ductal cell, male germ line stem cell (sensu Vertebrata) in testis
VANGL2	210	broad	marker	ganglionic eminence, buccal mucosa cell, ventricular zone
VANGL1	234	ubiquitous	marker	bronchial epithelial cell, corpus epididymis, caput epididymis
PARD3	278	ubiquitous	marker	cervix squamous epithelium, tongue squamous epithelium, secondary oocyte
RAD9B	159	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right testis
ARSG	135	ubiquitous	marker	blood, stromal cell of endometrium, monocyte
KMT5B	290	ubiquitous	marker	cortical plate, mucosa of paranasal sinus, visceral pleura
AMBRA1	279	ubiquitous	marker	oocyte, secondary oocyte, cervix squamous epithelium
FUZ	243	ubiquitous	marker	right uterine tube, right testis, left testis
DLC1	268	ubiquitous	marker	adrenal tissue, lower lobe of lung, sural nerve
SCRIB	134	ubiquitous	yes	lower esophagus mucosa, esophagus mucosa, right uterine tube
APAF1	254	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
ITGB1	303	ubiquitous	marker	visceral pleura, seminal vesicle, pleura
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ITGB1	5,325
APAF1	5,147
AMBRA1	4,380
MTHFR	3,492
PARD3	3,034
HECTD1	2,532
SHROOM3	2,075
VANGL1	1,864
VANGL2	1,763
KMT5B	1,384

Intra-cohort edges

A	B	Sources
VANGL1	VANGL2	biogrid_interaction

Structural data

PDB: 14 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TBXT	O15178	56
SCRIB	C0HLS1	42
ITGB1	P05556	22
APAF1	O14727	14
KMT5B	Q4FZB7	10
VANGL2	Q9ULK5	7
DLC1	Q96QB1	7
VANGL1	Q8TAA9	4
MTHFR	P42898	4
HECTD1	Q9ULT8	3
FUZ	Q9BT04	3
SHROOM3	Q8TF72	2
AMBRA1	Q9C0C7	2
PARD3	Q8TEW0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ARSG	Q96EG1	91.90
RAD9B	Q6WBX8	70.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 145. Enrichment computed across 16 evidence-associated genes (15 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RND3 GTPase cycle	3	51.9×	0.002	VANGL2, VANGL1, SCRIB
RND2 GTPase cycle	3	51.9×	0.002	VANGL2, VANGL1, SCRIB
RHOQ GTPase cycle	3	36.2×	0.003	VANGL1, DLC1, SCRIB
PCP/CE pathway	2	40.1×	0.032	VANGL2, SCRIB
CDC42 GTPase cycle	3	14.5×	0.032	VANGL1, DLC1, SCRIB
RND1 GTPase cycle	2	35.4×	0.034	VANGL2, VANGL1
RAC1 GTPase cycle	3	12.2×	0.035	VANGL1, DLC1, ITGB1
Asymmetric localization of PCP proteins	2	27.2×	0.040	VANGL2, SCRIB
RHOJ GTPase cycle	2	26.7×	0.040	VANGL1, SCRIB
RHOB GTPase cycle	2	20.6×	0.055	VANGL1, DLC1
RHOG GTPase cycle	2	19.8×	0.055	VANGL1, ITGB1
RHOC GTPase cycle	2	19.5×	0.055	VANGL1, DLC1
Localization of the PINCH-ILK-PARVIN complex to focal adhesions	1	190.3×	0.058	ITGB1
MET interacts with TNS proteins	1	152.3×	0.062	ITGB1
RAC2 GTPase cycle	2	16.9×	0.062	VANGL1, ITGB1
RAC3 GTPase cycle	2	15.9×	0.062	VANGL1, ITGB1
Activation of caspases through apoptosome-mediated cleavage	1	126.9×	0.066	APAF1
SMAC (DIABLO) binds to IAPs	1	108.8×	0.066	APAF1
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	108.8×	0.066	APAF1
SMAC, XIAP-regulated apoptotic response	1	108.8×	0.066	APAF1
Formation of apoptosome	1	95.2×	0.069	APAF1
Epithelial-Mesenchymal Transition (EMT) during gastrulation	1	95.2×	0.069	TBXT
Cytochrome c-mediated apoptotic response	1	84.6×	0.071	APAF1
CHL1 interactions	1	84.6×	0.071	ITGB1
Regulation of the apoptosome activity	1	69.2×	0.083	APAF1
TP53 Regulates Transcription of Caspase Activators and Caspases	1	63.4×	0.084	APAF1
Apoptotic factor-mediated response	1	58.6×	0.084	APAF1
The activation of arylsulfatases	1	58.6×	0.084	ARSG
Formation of axial mesoderm	1	54.4×	0.084	TBXT
Kidney development	1	54.4×	0.084	ITGB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neural tube closure	6	70.2×	4e-08	VANGL2, FUZ, DLC1, SCRIB, APAF1, MTHFR
establishment or maintenance of epithelial cell apical/basal polarity	3	109.0×	3e-04	VANGL2, PARD3, SCRIB
regulation of synapse pruning	2	263.3×	0.002	VANGL2, ITGB1
cardiac muscle cell myoblast differentiation	2	175.5×	0.003	TBXT, ITGB1
establishment of planar polarity	2	131.7×	0.005	VANGL2, FUZ
apical protein localization	2	123.9×	0.005	VANGL2, SHROOM3
negative regulation of Rho protein signal transduction	2	95.8×	0.006	DLC1, ITGB1
post-anal tail morphogenesis	2	91.6×	0.006	VANGL2, SCRIB
neural tube development	2	65.8×	0.011	AMBRA1, FUZ
Wnt signaling pathway, planar cell polarity pathway	2	56.9×	0.013	VANGL2, VANGL1
cell migration involved in kidney development	1	1053.2×	0.014	VANGL2
myoblast fate specification	1	1053.2×	0.014	ITGB1
response to G1 DNA damage checkpoint signaling	1	1053.2×	0.014	APAF1
negative regulation of neural crest formation	1	1053.2×	0.014	FUZ
hair follicle development	2	47.9×	0.014	VANGL2, FUZ
heart morphogenesis	2	46.8×	0.014	TBXT, DLC1
forebrain development	2	43.9×	0.014	DLC1, APAF1
regulation of collagen catabolic process	1	526.6×	0.017	ITGB1
response to vitamin B2	1	526.6×	0.017	MTHFR
cellular pigment accumulation	1	526.6×	0.017	SHROOM3
positive regulation of glutamate uptake involved in transmission of nerve impulse	1	526.6×	0.017	ITGB1
cardiac cell fate specification	1	526.6×	0.017	ITGB1
establishment of planar polarity involved in neural tube closure	1	526.6×	0.017	VANGL2
regulation of apoptotic DNA fragmentation	1	526.6×	0.017	APAF1
positive regulation of free ubiquitin chain polymerization	1	526.6×	0.017	AMBRA1
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	526.6×	0.017	FUZ
non-motile cilium assembly	2	36.3×	0.017	VANGL2, FUZ
cochlear nucleus development	1	351.1×	0.019	SCRIB
convergent extension involved in neural plate elongation	1	351.1×	0.019	VANGL2
dopaminergic neuron axon guidance	1	351.1×	0.019	VANGL2

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

3 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Ethinyl Estradiol	Phase 3
Folic Acid	Phase 3
Norgestimate	Phase 3

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 14

Druggability breadth: 6 of 16 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
APAF1	THONZONIUM BROMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APAF1	6	4
ITGB1	4	3
HECTD1	0	0
SHROOM3	0	0
TBXT	0	0
VANGL2	0	0
VANGL1	0	0
PARD3	0	0
RAD9B	0	0
ARSG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
THONZONIUM BROMIDE	4	APAF1
CEFIXIME	4	APAF1
DOXORUBICIN HYDROCHLORIDE	4	APAF1
METHYLENE BLUE ANHYDROUS	4	APAF1
CILENGITIDE	3	ITGB1
BENZETHONIUM CHLORIDE	2	APAF1
CALANOLIDE A	1	APAF1
GLPG-0187	1	ITGB1
GSK-3008348 FREE BASE	1	ITGB1
GSK-3008348	1	ITGB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ITGB1	409	Binding:376, Functional:32, ADMET:1
KMT5B	72	Binding:72
APAF1	10	Functional:8, Binding:2
ARSG	2	Binding:2
SHROOM3	1	Binding:1
TBXT	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ITGB1	409

Pharmacogenomics

Cohort genes with a PharmGKB record: 16; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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.

Compound	Max phase	Cohort target (bioactivity)
THONZONIUM BROMIDE	4	APAF1
CEFIXIME	4	APAF1
DOXORUBICIN HYDROCHLORIDE	4	APAF1
METHYLENE BLUE ANHYDROUS	4	APAF1
CILENGITIDE	3	ITGB1
BENZETHONIUM CHLORIDE	2	APAF1
CALANOLIDE A	1	APAF1
GLPG-0187	1	ITGB1
GSK-3008348 FREE BASE	1	ITGB1
GSK-3008348	1	ITGB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	APAF1
B	Phased (≥1) drug, not yet approved	1	ITGB1
C	Druggable family + PDB, no drug	1	MTHFR
D	Druggable family + AlphaFold only, no drug	1	ARSG
E	Difficult family or no structure, no drug	12	HECTD1, SHROOM3, TBXT, VANGL2, VANGL1, PARD3, RAD9B, KMT5B, AMBRA1, FUZ (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HECTD1	0	—
SHROOM3	1	—
TBXT	1	—
VANGL2	0	—
VANGL1	0	—
PARD3	0	—
RAD9B	0	—
ARSG	2	—
KMT5B	72	—
AMBRA1	0	—
FUZ	0	—
DLC1	0	—
SCRIB	0	—
MTHFR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 12.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	11
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02230072	PHASE1	COMPLETED	Fetoscopic Meningomyelocele Repair Study
NCT00966927	Not specified	ACTIVE_NOT_RECRUITING	Assessment of Functional Independence and Quality of Life in Adolescents With Spina Bifid
NCT02592291	Not specified	RECRUITING	Mobile Health Self-Management and Support System for Chronic and Complex Health Conditions
NCT03090633	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Repair of Isolated Fetal Spina Bifida
NCT05718440	Not specified	RECRUITING	Uronephrological Complications Risk Factors in Spinal Dysraphism
NCT06907732	Not specified	NOT_YET_RECRUITING	Fetoscopic Robotic Open Spina Bifida Treatment
NCT00060606	Not specified	COMPLETED	Management of Myelomeningocele Study (MOMS)
NCT00975338	Not specified	COMPLETED	The LETS Study: A Longitudinal Evaluation of Transition Services
NCT03044821	Not specified	TERMINATED	Open Myelomeningocele Repair With High Maternal BMI
NCT03544970	Not specified	COMPLETED	An Audit of the Posterior Fossa Characterization in Open Spina Bifida Based on Tertiary Center Experience
NCT04763382	Not specified	UNKNOWN	The Effect of Nursing Interventions for Clean Intermittent Catheterization Caregivers and Child
NCT05962086	Not specified	UNKNOWN	Determining Developmental and Clinical Markers Affecting Urinary Function of Children With Spinal Dysraphism

Cohort genes: HECTD1, SHROOM3, TBXT, VANGL2, VANGL1, PARD3, RAD9B, ARSG, KMT5B, AMBRA1, FUZ, DLC1, SCRIB, APAF1, ITGB1, MTHFR