Neural tube defects, folate-sensitive

Summary

Neural tube defects, folate-sensitive (MONDO:0011120) is a disease with 4 cohort genes. The dominant Reactome pathway is Metabolism of water-soluble vitamins and cofactors (4 cohort genes).

At a glance

• Cohort genes: 4
• ClinVar variants: 226

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neural tube defects, folate-sensitive
Mondo ID	MONDO:0011120
MeSH	C536409
OMIM	601634
UMLS	C1866558
MedGen	355746
GARD	0024774
Is cancer (heuristic)	no

Also known as: neural tube defects, folate-sensitive · NTDFS

Data availability: 226 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › spina bifida › isolated spina bifida › neural tube defects, folate-sensitive

Related subtypes (3): neural tube defects, X-linked, spina bifida aperta, spina bifida cystica

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

226 retrieved; paginated sample, class counts are floors:

93 likely pathogenic, 63 pathogenic/likely pathogenic, 24 conflicting classifications of pathogenicity, 19 uncertain significance, 15 pathogenic, 6 benign/likely benign, 2 likely benign, 1 benign, 1 pathogenic; risk factor, 1 drug response, 1 benign/likely benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
2813712	NM_005956.4(MTHFD1):c.153_154del (p.Ile53fs)	MTHFD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446302	NM_005956.4(MTHFD1):c.727+1G>A	MTHFD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
446306	NM_005956.4(MTHFD1):c.146C>T (p.Ser49Phe)	MTHFD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1004148	NM_005957.5(MTHFR):c.1166+5G>C	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1024006	NM_005957.5(MTHFR):c.1228_1242del (p.Ser410_Lys414del)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048667	NM_005957.5(MTHFR):c.584C>T (p.Ala195Val)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066378	NM_005957.5(MTHFR):c.1750A>T (p.Lys584Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066379	NM_005957.5(MTHFR):c.474A>T (p.Gly158=)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068525	NM_005957.5(MTHFR):c.202C>T (p.Arg68Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1363312	NM_005957.5(MTHFR):c.1768del (p.Leu590fs)	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
1445597	NM_005957.5(MTHFR):c.523G>A (p.Ala175Thr)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452521	NM_005957.5(MTHFR):c.273dup (p.Asp92fs)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452549	NM_005957.5(MTHFR):c.1069C>T (p.Arg357Cys)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1675344	NM_005957.5(MTHFR):c.1500G>A (p.Trp500Ter)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187869	NM_005957.5(MTHFR):c.202C>G (p.Arg68Gly)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187872	NM_005957.5(MTHFR):c.337G>A (p.Ala113Thr)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187876	NM_005957.5(MTHFR):c.548G>A (p.Arg183Gln)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187891	NM_005957.5(MTHFR):c.1167-2del	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
187892	NM_005957.5(MTHFR):c.1262G>C (p.Trp421Ser)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187893	NM_005957.5(MTHFR):c.1320G>A (p.Ser440=)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187897	NM_005957.5(MTHFR):c.1632+2T>G	MTHFR	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
187900	NM_005957.5(MTHFR):c.1752+1G>T	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
187901	NM_005957.5(MTHFR):c.1753-18G>A	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2177759	NM_005957.5(MTHFR):c.781-1G>A	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
2676843	NM_005957.5(MTHFR):c.1347+1G>A	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
2676851	NM_005957.5(MTHFR):c.237-2A>G	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
2779949	NM_005957.5(MTHFR):c.1142G>A (p.Trp381Ter)	MTHFR	Pathogenic	criteria provided, multiple submitters, no conflicts
3239802	NM_005957.5(MTHFR):c.781-2A>G	MTHFR	Pathogenic	criteria provided, single submitter
3239807	NM_005957.5(MTHFR):c.1488del (p.Ile497fs)	MTHFR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTHFD1	Orphanet:658813	Combined immunodeficiency-megaloblastic anemia due to methylenetetrahydrofolate dehydrogenase 1 deficiency
MTHFR	Orphanet:395	Homocystinuria due to methylene tetrahydrofolate reductase deficiency
MTHFR	Orphanet:563609	Isolated anencephaly
MTHFR	Orphanet:563612	Isolated exencephaly
MTR	Orphanet:2170	Methylcobalamin deficiency type cblG
MTRR	Orphanet:2169	Methylcobalamin deficiency type cblE

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTHFD1	HGNC:7432	ENSG00000100714	P11586	C-1-tetrahydrofolate synthase, cytoplasmic	clinvar
MTHFR	HGNC:7436	ENSG00000177000	P42898	Methylenetetrahydrofolate reductase (NADPH)	clinvar
MTR	HGNC:7468	ENSG00000116984	Q99707	Methionine synthase	clinvar
MTRR	HGNC:7473	ENSG00000124275	Q9UBK8	Methionine synthase reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTHFD1	C-1-tetrahydrofolate synthase, cytoplasmic	Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate.
MTHFR	Methylenetetrahydrofolate reductase (NADPH)	Catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine.
MTR	Methionine synthase	Catalyzes the transfer of a methyl group from methylcob(III)alamin (MeCbl) to homocysteine, yielding enzyme-bound cob(I)alamin and methionine in the cytosol.
MTRR	Methionine synthase reductase	Key enzyme in methionine and folate homeostasis responsible for the reactivation of methionine synthase (MTR/MS) activity by catalyzing the reductive methylation of MTR-bound cob(II)alamin.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	4	12.0×	5e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTHFD1	Enzyme (other)	yes	1.5.1.5	Formate_THF_ligase, THF_DH/CycHdrlase, Formate_THF_ligase_CS
MTHFR	Enzyme (other)	yes	1.5.1.20	Mehydrof_redctse-like, Fadh2_euk, FAD-linked_oxidoreductase-like
MTR	Enzyme (other)	yes	2.1.1.13	Pterin-binding_dom, HCY_dom, Cbl-bd_cap
MTRR	Enzyme (other)	yes	1.16.1.8	Flavdoxin-like, OxRdtase_FAD/NAD-bd, Flavoprot_Pyr_Nucl_cyt_Rdtase

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
corpus epididymis	2
liver	1
right lobe of liver	1
ventricular zone	1
apex of heart	1
sural nerve	1
caput epididymis	1
decidua	1
choroid plexus epithelium	1
endothelial cell	1
pancreatic ductal cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTHFD1	289	ubiquitous	marker	right lobe of liver, liver, ventricular zone
MTHFR	254	ubiquitous	marker	corpus epididymis, sural nerve, apex of heart
MTR	294	ubiquitous	marker	caput epididymis, corpus epididymis, decidua
MTRR	291	ubiquitous	marker	endothelial cell, pancreatic ductal cell, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTHFR	3,492
MTHFD1	3,191
MTR	2,607
MTRR	1,455

Intra-cohort edges

A	B	Sources
MTHFD1	MTHFR	string_interaction
MTHFD1	MTR	string_interaction
MTHFD1	MTRR	string_interaction
MTHFR	MTR	string_interaction
MTHFR	MTRR	string_interaction
MTR	MTRR	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTHFD1	P11586	12
MTR	Q99707	9
MTHFR	P42898	4
MTRR	Q9UBK8	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 22. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of water-soluble vitamins and cofactors	4	181.3×	2e-08	MTHFD1, MTHFR, MTR, MTRR
Metabolism of vitamins and cofactors	4	116.5×	6e-08	MTHFD1, MTHFR, MTR, MTRR
Defective MTRR causes HMAE	2	2855.0×	5e-07	MTR, MTRR
Defective MTR causes HMAG	2	2855.0×	5e-07	MTR, MTRR
Cobalamin (Cbl) metabolism	2	634.4×	1e-05	MTR, MTRR
Methylation	2	407.9×	3e-05	MTR, MTRR
Defects in cobalamin (B12) metabolism	2	407.9×	3e-05	MTR, MTRR
Cobalamin (Cbl, vitamin B12) transport and metabolism	2	317.2×	3e-05	MTR, MTRR
Metabolism of folate and pterines	2	317.2×	3e-05	MTHFD1, MTHFR
Defects in vitamin and cofactor metabolism	2	300.5×	3e-05	MTR, MTRR
Sulfur amino acid metabolism	2	285.5×	3e-05	MTR, MTRR
Metabolism	4	11.6×	1e-04	MTHFD1, MTHFR, MTR, MTRR
Phase II - Conjugation of compounds	2	139.3×	1e-04	MTR, MTRR
Biological oxidations	2	64.9×	5e-04	MTR, MTRR
Diseases of metabolism	2	40.2×	0.001	MTR, MTRR
Metabolism of amino acids and derivatives	2	33.8×	0.002	MTR, MTRR
RHOH GTPase cycle	1	77.2×	0.017	MTR
Disease	2	6.5×	0.039	MTR, MTRR
RHO GTPase cycle	1	15.0×	0.075	MTR
Signaling by Rho GTPases	1	8.6×	0.120	MTR
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.120	MTR
Signal Transduction	1	2.5×	0.339	MTR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete methionine biosynthetic process	4	3370.4×	5e-14	MTHFD1, MTHFR, MTR, MTRR
homocysteine metabolic process	3	1404.3×	7e-09	MTHFR, MTR, MTRR
L-methionine metabolic process	2	1404.3×	7e-06	MTHFD1, MTHFR
tetrahydrofolate interconversion	2	842.6×	2e-05	MTHFD1, MTHFR
cobalamin metabolic process	2	766.0×	2e-05	MTR, MTRR
folic acid metabolic process	2	561.7×	2e-05	MTHFD1, MTRR
neural tube closure	2	93.6×	8e-04	MTHFD1, MTHFR
sulfur amino acid metabolic process	1	4213.0×	9e-04	MTR
purine ribonucleotide biosynthetic process	1	4213.0×	9e-04	MTHFD1
10-formyltetrahydrofolate biosynthetic process	1	2106.5×	0.001	MTHFD1
response to vitamin B2	1	2106.5×	0.001	MTHFR
L-homocysteine catabolic process	1	1404.3×	0.002	MTRR
S-adenosylmethionine metabolic process	1	1404.3×	0.002	MTHFR
transsulfuration	1	1053.2×	0.002	MTHFD1
L-methionine cycle	1	1053.2×	0.002	MTRR
tetrahydrofolate metabolic process	1	601.9×	0.003	MTR
response to folic acid	1	601.9×	0.003	MTHFR
embryonic neurocranium morphogenesis	1	468.1×	0.004	MTHFD1
embryonic viscerocranium morphogenesis	1	421.3×	0.004	MTHFD1
neutrophil homeostasis	1	383.0×	0.004	MTHFD1
purine nucleotide biosynthetic process	1	324.1×	0.005	MTHFD1
heterochromatin organization	1	324.1×	0.005	MTHFR
axon regeneration	1	280.9×	0.005	MTR
somite development	1	280.9×	0.005	MTHFD1
response to amino acid	1	247.8×	0.005	MTHFR
cellular response to nitric oxide	1	234.1×	0.005	MTR
response to axon injury	1	127.7×	0.009	MTR
response to interleukin-1	1	127.7×	0.009	MTHFR
methylation	1	42.6×	0.027	MTR
response to hypoxia	1	23.9×	0.045	MTHFR

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
MTR	LOMITAPIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTHFD1	1	2
MTR	1	4
MTHFR	0	0
MTRR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LOMITAPIDE	4	MTR
KETOTREXATE	2	MTHFD1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
MTHFD1	30	Binding:30
MTR	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTHFD1	1.5.1.5, 3.5.4.9, 6.3.3.2, 6.3.4.3	methylenetetrahydrofolate dehydrogenase (NADP+), methenyltetrahydrofolate cyclohydrolase, 5-formyltetrahydrofolate cyclo-ligase, formate-tetrahydrofolate ligase
MTHFR	1.5.1.20, 1.5.1.53	methylenetetrahydrofolate reductase [NAD(P)H], methylenetetrahydrofolate reductase (NADPH)
MTR	2.1.1.13	methionine synthase
MTRR	1.16.1.8	[methionine synthase] reductase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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)
LOMITAPIDE	4	MTR
KETOTREXATE	2	MTHFD1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MTR
B	Phased (≥1) drug, not yet approved	1	MTHFD1
C	Druggable family + PDB, no drug	2	MTHFR, MTRR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
MTHFR	0	MTR
MTRR	0	MTR

Clinical trials & evidence

Clinical trials

Clinical trials: 0.