Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Summary

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (MONDO:0032684) is a disease caused by POLE (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: POLE (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 349

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency
Mondo ID	MONDO:0032684
OMIM	618336
UMLS	C5193036
MedGen	1684464
GARD	0025721
Is cancer (heuristic)	no

Also known as: IMAGE-I syndrome · IMAGEI

Data availability: 349 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 › skeletal dysplasia › primordial dwarfism and slender bone disorder › intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency

Related subtypes (25): microcephalic osteodysplastic primordial dwarfism type II, Lowry-Wood syndrome, Hallermann-Streiff syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, microcephalic primordial dwarfism, Toriello type, 3M syndrome 1, osteocraniostenosis, Seckel syndrome 2, 3M syndrome 2, Seckel syndrome 5, 3M syndrome 3, IMAGe syndrome, short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome, microcephalic primordial dwarfism, Alazami type, Rothmund-Thomson syndrome type 3, Seckel syndrome 8, microcephaly 13, primary, autosomal recessive, short stature, microcephaly, and endocrine dysfunction, Roifman syndrome, Seckel syndrome 9, Seckel syndrome 10, Kenny-Caffey syndrome, microcephalic osteodysplastic primordial dwarfism types I and III, microcephalic primordial dwarfism due to RTTN deficiency, microcephalic osteodysplastic dysplasia, Saul-Wilson type

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

349 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 107 conflicting classifications of pathogenicity, 35 likely benign, 26 benign/likely benign, 18 benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1804889	NM_006231.4(POLE):c.6571C>T (p.Gln2191Ter)	POLE	Pathogenic	criteria provided, single submitter
587359	NM_006231.4(POLE):c.141del (p.Phe48fs)	POLE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
619085	NM_006231.4(POLE):c.1686+32C>G	POLE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1676477	NM_006231.4(POLE):c.6398_6407del (p.Val2133fs)	POLE	Likely pathogenic	criteria provided, single submitter
2431193	NM_006231.4(POLE):c.3392del (p.Asp1131fs)	POLE	Likely pathogenic	criteria provided, single submitter
3767243	NM_006231.4(POLE):c.330G>A (p.Lys110=)	POLE	Likely pathogenic	criteria provided, single submitter
246154	NM_006231.4(POLE):c.2T>C (p.Met1Thr)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405608	NM_006231.4(POLE):c.1A>G (p.Met1Val)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
422515	NM_006231.4(POLE):c.-47G>T	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
957998	NM_006231.4(POLE):c.20G>A (p.Gly7Glu)	LOC130009266	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036273	NM_006231.4(POLE):c.5908T>C (p.Ser1970Pro)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1050781	NM_006231.4(POLE):c.4375G>T (p.Glu1459Ter)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1461993	NM_006231.4(POLE):c.3668C>T (p.Pro1223Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1738116	NM_006231.4(POLE):c.4136C>T (p.Ala1379Val)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1755247	NM_006231.4(POLE):c.6754A>C (p.Met2252Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221000	NM_006231.4(POLE):c.861T>A (p.Asp287Glu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
221094	NM_006231.4(POLE):c.2706+5G>A	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240371	NM_006231.4(POLE):c.1015G>A (p.Asp339Asn)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240374	NM_006231.4(POLE):c.1064A>G (p.Lys355Arg)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240396	NM_006231.4(POLE):c.154C>T (p.Arg52Trp)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240397	NM_006231.4(POLE):c.1583C>T (p.Thr528Met)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240415	NM_006231.4(POLE):c.1A>T (p.Met1Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240419	NM_006231.4(POLE):c.2083T>C (p.Phe695Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240421	NM_006231.4(POLE):c.2089C>G (p.Pro697Ala)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240436	NM_006231.4(POLE):c.2599G>A (p.Val867Ile)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240446	NM_006231.4(POLE):c.2792T>C (p.Phe931Ser)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240461	NM_006231.4(POLE):c.3245G>A (p.Arg1082His)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240478	NM_006231.4(POLE):c.3778G>A (p.Ala1260Thr)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240486	NM_006231.4(POLE):c.3890C>T (p.Ser1297Leu)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240495	NM_006231.4(POLE):c.3971G>A (p.Arg1324His)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
POLE	Strong	Autosomal recessive	facial dysmorphism-immunodeficiency-livedo-short stature syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLE	Orphanet:352712	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
POLE	Orphanet:440437	Familial colorectal cancer Type X
POLE	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:85173	IMAGe syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	gencc,clinvar
EXOC4	HGNC:30389	ENSG00000131558	Q96A65	Exocyst complex component 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.
EXOC4	Exocyst complex component 4	Component of the exocyst complex involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf
EXOC4	Other/Unknown	no		Sec8_exocyst_N, Sec8/EXOC4, Sec8_M

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right testis	1
bone marrow cell	1
calcaneal tendon	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere
EXOC4	261	ubiquitous	marker	bone marrow cell, cortical plate, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLE	3,267
EXOC4	2,865

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLE	Q07864	18
EXOC4	Q96A65	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication initiation	1	713.8×	0.010	POLE
VxPx cargo-targeting to cilium	1	259.6×	0.010	EXOC4
PCNA-Dependent Long Patch Base Excision Repair	1	259.6×	0.010	POLE
Insulin processing	1	228.4×	0.010	EXOC4
Gap-filling DNA repair synthesis and ligation in GG-NER	1	219.6×	0.010	POLE
Recognition of DNA damage by PCNA-containing replication complex	1	190.3×	0.010	POLE
Termination of translesion DNA synthesis	1	173.0×	0.010	POLE
Activation of the pre-replicative complex	1	163.1×	0.010	POLE
Dual Incision in GG-NER	1	129.8×	0.011	POLE
HDR through Homologous Recombination (HRR)	1	95.2×	0.012	POLE
Gap-filling DNA repair synthesis and ligation in TC-NER	1	89.2×	0.012	POLE
Dual incision in TC-NER	1	86.5×	0.012	POLE
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	77.2×	0.013	EXOC4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA replication proofreading	1	2808.7×	0.004	POLE
leading strand elongation	1	2106.5×	0.004	POLE
paraxial mesoderm formation	1	1685.2×	0.004	EXOC4
nucleotide-excision repair, DNA gap filling	1	1404.3×	0.004	POLE
obsolete vesicle tethering involved in exocytosis	1	936.2×	0.004	EXOC4
protein transmembrane transport	1	648.1×	0.005	EXOC4
base-excision repair, gap-filling	1	561.7×	0.005	POLE
DNA synthesis involved in DNA repair	1	468.1×	0.005	POLE
obsolete vesicle docking involved in exocytosis	1	337.0×	0.006	EXOC4
DNA-templated DNA replication	1	280.9×	0.006	POLE
Golgi to plasma membrane transport	1	280.9×	0.006	EXOC4
embryonic organ development	1	240.7×	0.007	POLE
membrane fission	1	205.5×	0.007	EXOC4
regulation of macroautophagy	1	147.8×	0.010	EXOC4
mitotic cytokinesis	1	129.6×	0.010	EXOC4
G1/S transition of mitotic cell cycle	1	100.3×	0.012	POLE
DNA replication	1	82.6×	0.014	POLE
exocytosis	1	75.9×	0.015	EXOC4
mitotic cell cycle	1	66.9×	0.016	POLE
chemical synaptic transmission	1	38.6×	0.026	EXOC4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
POLE	0	0
EXOC4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EXOC4	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLE	2.7.7.7	DNA-directed DNA polymerase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	POLE, EXOC4

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)
POLE	0	—
EXOC4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.