Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

Summary

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination (MONDO:0032705) is a disease caused by MTHFS (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MTHFS (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination
Mondo ID	MONDO:0032705
OMIM	618367
Orphanet	597874
UMLS	C5193057
MedGen	1684142
GARD	0018018
Is cancer (heuristic)	no

Also known as: 5,10-methenyltetrahydrofolate synthetase deficiency · MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome · NEDMEHM · NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, EPILEPSY, AND HYPOMYELINATION

Data availability: 7 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › disorder of metabolite absorption and transport › disorder of vitamin and non-protein cofactor absorption and transport › disorder of folate metabolism and transport › neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

Related subtypes (6): hereditary folate malabsorption, formiminoglutamic aciduria, homocystinuria due to methylene tetrahydrofolate reductase deficiency, neurodegenerative syndrome due to cerebral folate transport deficiency, constitutional megaloblastic anemia with severe neurologic disease, megaloblastic anemia-immunodeficiency due to folate transporter 1 deficiency

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

7 retrieved; paginated sample, class counts are floors:

3 pathogenic, 2 likely pathogenic, 1 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1344538	NM_006441.4(MTHFS):c.316A>T (p.Lys106Ter)	MTHFS	Pathogenic	criteria provided, single submitter
2875670	NM_006441.4(MTHFS):c.10_25dup (p.Ala9fs)	MTHFS	Pathogenic	criteria provided, multiple submitters, no conflicts
624594	NM_006441.4(MTHFS):c.107T>C (p.Leu36Pro)	MTHFS	Pathogenic	no assertion criteria provided
3775227	NM_006441.4(MTHFS):c.9_18dup (p.Ser7fs)	MTHFS	Likely pathogenic	criteria provided, single submitter
522830	NM_006441.4(MTHFS):c.484C>T (p.Gln162Ter)	MTHFS	Likely pathogenic	criteria provided, single submitter
522831	NM_006441.4(MTHFS):c.434G>A (p.Arg145Gln)	MTHFS	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3776268	NM_006441.4(MTHFS):c.117+100C>G	MTHFS	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

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

Gene	Classification	Inheritance	Disease	Records
MTHFS	Strong	Autosomal recessive	neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTHFS	Orphanet:597874	MTHFS-related developmental delay-microcephaly-short stature-epilepsy syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTHFS	HGNC:7437	ENSG00000136371	P49914	5-formyltetrahydrofolate cyclo-ligase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTHFS	5-formyltetrahydrofolate cyclo-ligase	Contributes to tetrahydrofolate metabolism.

Protein-family classification

Druggable: 1 · 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)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTHFS	Enzyme (other)	yes	6.3.3.2	FTHF_cligase, FTHF_cligase-like_sf, NagB/RpiA_transferase-like

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

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

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTHFS	137	ubiquitous	marker	right lobe of liver, liver, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTHFS	971

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTHFS	P49914	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism of folate and pterines	1	634.4×	0.006	MTHFS
Metabolism of water-soluble vitamins and cofactors	1	181.3×	0.011	MTHFS
Metabolism of vitamins and cofactors	1	116.5×	0.011	MTHFS
Metabolism	1	11.6×	0.086	MTHFS

GO biological processes by enrichment

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

GO term	Cohort genes	Fold	FDR	Sample cohort genes
folic acid-containing compound biosynthetic process	1	16852.0×	2e-04	MTHFS
folic acid catabolic process	1	16852.0×	2e-04	MTHFS
formate metabolic process	1	8426.0×	3e-04	MTHFS
tetrahydrofolate metabolic process	1	2407.4×	7e-04	MTHFS
tetrahydrofolate interconversion	1	1685.2×	8e-04	MTHFS
glutamate metabolic process	1	1123.5×	9e-04	MTHFS
folic acid metabolic process	1	1123.5×	9e-04	MTHFS

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTHFS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTHFS	6.3.3.2	5-formyltetrahydrofolate cyclo-ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

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

Druggability pyramid

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

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MTHFS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.