MEHMO syndrome

Summary

MEHMO syndrome (MONDO:0010258) is a disease caused by EIF2S3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EIF2S3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 21
• Phenotypes (HPO): 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		22	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000054	Micropenis	Very frequent (80-99%)
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000311	Round face	Very frequent (80-99%)
HP:0000340	Sloping forehead	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0003241	External genital hypoplasia	Very frequent (80-99%)
HP:0008736	Hypoplasia of penis	Very frequent (80-99%)
HP:0009748	Large earlobe	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0012471	Thick vermilion border	Very frequent (80-99%)
HP:0000293	Full cheeks	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0000713	Agitation	Frequent (30-79%)
HP:0001182	Tapered finger	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002714	Downturned corners of mouth	Frequent (30-79%)
HP:0000819	Diabetes mellitus	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	MEHMO syndrome
Mondo ID	MONDO:0010258
MeSH	C537451
OMIM	300148, 300987
Orphanet	85282
DOID	DOID:0060801
ICD-11	500681653
SNOMED CT	722037004
UMLS	C1846278
MedGen	375855
GARD	0009178
Is cancer (heuristic)	no

Also known as: intellectual disability, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity · intellectual disability, X-linked, syndromic 20 · intellectual disability, X-linked, syndromic 25 · intellectual disability, X-linked, syndromic, Borck type · intellectual disability, X-linked, syndromic, Borck type; MRXSBRK · MEHMO · MEHMO syndrome · MEHMO syndrome, X-linked recessive · mental retardation, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity · mental retardation, X-linked, syndromic 20 · mental retardation, X-linked, syndromic 25 · mental retardation, X-linked, syndromic, Borck type · MRXS20 · MRXS25 · MRXSBRK · syndromic X-linked intellectual disability 20 · syndromic X-linked intellectual disability 25 · X-linked intellectual disability-epileptic seizures-hypogenitalism-microcephaly-obesity syndrome · X-linked MEHMO syndrome

Data availability: 21 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › MEHMO syndrome

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

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

21 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686856	NM_001415.4(EIF2S3):c.1294C>T (p.Pro432Ser)	EIF2S3	Pathogenic	no assertion criteria provided
265789	NM_001415.4(EIF2S3):c.1394_1397del (p.Ile465fs)	EIF2S3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
267205	NM_001415.4(EIF2S3):c.665T>C (p.Ile222Thr)	EIF2S3	Pathogenic	no assertion criteria provided
267206	NM_001415.4(EIF2S3):c.777T>G (p.Ile259Met)	EIF2S3	Pathogenic	no assertion criteria provided
1077096	NM_001415.4(EIF2S3):c.820C>G (p.Leu274Val)	EIF2S3	Likely pathogenic	criteria provided, single submitter
3024228	NM_001415.4(EIF2S3):c.620T>C (p.Ile207Thr)	EIF2S3	Likely pathogenic	criteria provided, single submitter
488501	NM_001415.4(EIF2S3):c.431C>T (p.Thr144Ile)	EIF2S3	Likely pathogenic	criteria provided, single submitter
804299	NM_001415.4(EIF2S3):c.433A>G (p.Met145Val)	EIF2S3	Likely pathogenic	criteria provided, single submitter
1253858	NM_001415.4(EIF2S3):c.1003G>A (p.Gly335Ser)	EIF2S3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1878657	NM_001415.4(EIF2S3):c.1046G>A (p.Arg349Gln)	EIF2S3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3384186	NM_001415.4(EIF2S3):c.*109G>A	EIF2S3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033838	NM_001415.4(EIF2S3):c.1183-15A>G	EIF2S3	Uncertain significance	criteria provided, single submitter
1065472	NM_001415.4(EIF2S3):c.1403C>G (p.Thr468Arg)	EIF2S3	Uncertain significance	criteria provided, single submitter
2585434	NM_001415.4(EIF2S3):c.717A>G (p.Ile239Met)	EIF2S3	Uncertain significance	criteria provided, single submitter
2627784	NM_001415.4(EIF2S3):c.65C>T (p.Thr22Ile)	EIF2S3	Uncertain significance	no assertion criteria provided
265790	NM_001415.4(EIF2S3):c.324T>A (p.Ser108Arg)	EIF2S3	Uncertain significance	criteria provided, single submitter
3234985	NM_001415.4(EIF2S3):c.938C>T (p.Pro313Leu)	EIF2S3	Uncertain significance	criteria provided, single submitter
3370410	NM_001415.4(EIF2S3):c.353C>T (p.Pro118Leu)	EIF2S3	Uncertain significance	criteria provided, single submitter
3731411	NM_001415.4(EIF2S3):c.868G>A (p.Val290Met)	EIF2S3	Uncertain significance	criteria provided, single submitter
3775442	NM_001415.4(EIF2S3):c.1304C>T (p.Thr435Ile)	EIF2S3	Uncertain significance	criteria provided, single submitter
128994	NM_001415.4(EIF2S3):c.99C>T (p.His33=)	EIF2S3	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
EIF2S3	Definitive	X-linked	MEHMO syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EIF2S3	Orphanet:85282	MEHMO 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
EIF2S3	HGNC:3267	ENSG00000130741	P41091	Eukaryotic translation initiation factor 2 subunit 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EIF2S3	Eukaryotic translation initiation factor 2 subunit 3	Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA.

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)
EIF2S3	Enzyme (other)	yes	3.6.5.3	T_Tr_GTP-bd_dom, EFTu-like_2, Transl_B-barrel_sf

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
germinal epithelium of ovary	1
oviduct epithelium	1
parietal pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EIF2S3	261	ubiquitous	marker	germinal epithelium of ovary, oviduct epithelium, parietal pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2S3	3,709

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2S3	P41091	25

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Recycling of eIF2:GDP	1	1268.9×	0.004	EIF2S3
Cellular response to mitochondrial stress	1	1142.0×	0.004	EIF2S3
PERK regulates gene expression	1	815.7×	0.004	EIF2S3
Response of EIF2AK1 (HRI) to heme deficiency	1	713.8×	0.004	EIF2S3
Formation of the ternary complex, and subsequently, the 43S complex	1	215.5×	0.009	EIF2S3
Translation initiation complex formation	1	190.3×	0.009	EIF2S3
Ribosomal scanning and start codon recognition	1	190.3×	0.009	EIF2S3
PKR-mediated signaling	1	141.0×	0.010	EIF2S3
ABC-family protein mediated transport	1	121.5×	0.010	EIF2S3
Response of EIF2AK4 (GCN2) to amino acid deficiency	1	110.9×	0.010	EIF2S3
L13a-mediated translational silencing of Ceruloplasmin expression	1	101.1×	0.010	EIF2S3
GTP hydrolysis and joining of the 60S ribosomal subunit	1	100.2×	0.010	EIF2S3

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
formation of translation preinitiation complex	1	1532.0×	0.001	EIF2S3
cytoplasmic translational initiation	1	1404.3×	0.001	EIF2S3
translational initiation	1	358.6×	0.003	EIF2S3

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
EIF2S3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EIF2S3	3.6.5.3	protein-synthesizing GTPase

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	EIF2S3
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)
EIF2S3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.