Microcephaly, epilepsy, and diabetes syndrome 1

Summary

Microcephaly, epilepsy, and diabetes syndrome 1 (MONDO:0031481) is a disease caused by IER3IP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: IER3IP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	microcephaly, epilepsy, and diabetes syndrome 1
Mondo ID	MONDO:0031481
OMIM	614231
Orphanet	306558
GARD	0018438
Is cancer (heuristic)	no

Also known as: MEDS1 · microcephaly, epilepsy, and diabetes syndrome · primary microcephaly-epilepsy-permanent neonatal diabetes syndrome

Data availability: 6 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 › microcephaly, epilepsy, and diabetes syndrome › microcephaly, epilepsy, and diabetes syndrome 1

Related subtypes (1): microcephaly, epilepsy, and diabetes syndrome 2

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

6 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
30786	NM_016097.5(IER3IP1):c.233T>C (p.Leu78Pro)	IER3IP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
759569	NM_016097.5(IER3IP1):c.92-10C>T	IER3IP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051191	NM_016097.5(IER3IP1):c.30G>T (p.Gln10His)	IER3IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372794	NM_016097.5(IER3IP1):c.137C>T (p.Pro46Leu)	IER3IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
208459	NM_016097.5(IER3IP1):c.80del (p.Phe27fs)	IER3IP1	Uncertain significance	criteria provided, single submitter
30785	NM_016097.5(IER3IP1):c.62T>G (p.Val21Gly)	IER3IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
IER3IP1	Strong	Autosomal recessive	primary microcephaly-epilepsy-permanent neonatal diabetes syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IER3IP1	Orphanet:306558	Primary microcephaly-epilepsy-permanent neonatal diabetes 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
IER3IP1	HGNC:18550	ENSG00000134049	Q9Y5U9	Immediate early response 3-interacting protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IER3IP1	Immediate early response 3-interacting protein 1	Regulator of endoplasmic reticulum secretion that acts as a key determinant of brain size.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IER3IP1	Other/Unknown	no		Yos1

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
kidney epithelium	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IER3IP1	262	ubiquitous	marker	oocyte, secondary oocyte, kidney epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IER3IP1	1,230

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IER3IP1	Q9Y5U9	61.57

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
positive regulation of extracellular matrix constituent secretion	1	5617.3×	0.001	IER3IP1
regulation of fibroblast apoptotic process	1	5617.3×	0.001	IER3IP1
insulin metabolic process	1	2407.4×	0.002	IER3IP1
type B pancreatic cell differentiation	1	2106.5×	0.002	IER3IP1
organ growth	1	732.7×	0.004	IER3IP1
cell maturation	1	443.5×	0.005	IER3IP1
endoplasmic reticulum organization	1	421.3×	0.005	IER3IP1
positive regulation of protein secretion	1	343.9×	0.006	IER3IP1
endoplasmic reticulum to Golgi vesicle-mediated transport	1	135.9×	0.012	IER3IP1
glucose homeostasis	1	130.6×	0.012	IER3IP1
chromatin organization	1	99.1×	0.015	IER3IP1
gene expression	1	79.9×	0.015	IER3IP1
brain development	1	79.5×	0.015	IER3IP1
protein transport	1	43.9×	0.025	IER3IP1
negative regulation of cell population proliferation	1	42.1×	0.025	IER3IP1
negative regulation of apoptotic process	1	34.8×	0.029	IER3IP1

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
IER3IP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	IER3IP1

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)
IER3IP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.