Periventricular heterotopia with microcephaly, autosomal recessive

Summary

Periventricular heterotopia with microcephaly, autosomal recessive (MONDO:0011966) is a disease caused by ARFGEF2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: ARFGEF2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 181

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	periventricular heterotopia with microcephaly, autosomal recessive
Mondo ID	MONDO:0011966
MeSH	C564292
OMIM	608097
UMLS	C1842563
MedGen	334110
GARD	0015424
Is cancer (heuristic)	no

Also known as: ARPHM · periventricular heterotopia with microcephaly, autosomal recessive

Data availability: 181 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › periventricular nodular heterotopia › periventricular heterotopia with microcephaly, autosomal recessive

Related subtypes (7): heterotopia, periventricular, X-linked dominant, heterotopia, periventricular, associated with chromosome 5P anomalies, chromosome 5Q14.3 deletion syndrome, distal, periventricular nodular heterotopia 6, periventricular nodular heterotopia 7, periventricular nodular heterotopia 9, periventricular nodular heterotopia 8

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

181 retrieved; paginated sample, class counts are floors:

112 uncertain significance, 35 conflicting classifications of pathogenicity, 13 benign, 8 pathogenic, 5 likely benign, 5 likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
5051	NM_006420.3(ARFGEF2):c.[242C>A;247_249delinsTT]		Pathogenic	no assertion criteria provided
1323380	NM_006420.3(ARFGEF2):c.1072C>T (p.Gln358Ter)	ARFGEF2	Pathogenic	criteria provided, single submitter
1705394	NM_006420.3(ARFGEF2):c.4003G>T (p.Glu1335Ter)	ARFGEF2	Pathogenic	criteria provided, single submitter
3254661	NM_006420.3(ARFGEF2):c.4918C>T (p.Arg1640Ter)	ARFGEF2	Pathogenic	criteria provided, single submitter
434297	NM_006420.3(ARFGEF2):c.2638_2639delinsT (p.Pro880fs)	ARFGEF2	Pathogenic	criteria provided, single submitter
803610	NM_006420.3(ARFGEF2):c.1492del (p.Met498fs)	ARFGEF2	Pathogenic	criteria provided, single submitter
803611	NM_006420.3(ARFGEF2):c.5254C>T (p.Arg1752Ter)	ARFGEF2	Pathogenic	criteria provided, single submitter
89028	NM_006420.3(ARFGEF2):c.1958+1G>A	ARFGEF2	Pathogenic	no assertion criteria provided
2434911	NM_006420.3(ARFGEF2):c.2821C>T (p.Arg941Ter)	ARFGEF2	Likely pathogenic	criteria provided, single submitter
2585457	NM_006420.3(ARFGEF2):c.91C>T (p.Gln31Ter)	ARFGEF2	Likely pathogenic	criteria provided, single submitter
4278356	NM_006420.3(ARFGEF2):c.3487C>T (p.Gln1163Ter)	ARFGEF2	Likely pathogenic	criteria provided, single submitter
4293168	NM_006420.3(ARFGEF2):c.1346dup (p.Pro449_Asp450insTer)	ARFGEF2	Likely pathogenic	criteria provided, single submitter
930714	NM_006420.3(ARFGEF2):c.4269del (p.Leu1424fs)	ARFGEF2	Likely pathogenic	criteria provided, single submitter
128427	NM_006420.3(ARFGEF2):c.1275C>T (p.His425=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128432	NM_006420.3(ARFGEF2):c.1644G>A (p.Glu548=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128433	NM_006420.3(ARFGEF2):c.169C>T (p.Pro57Ser)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128434	NM_006420.3(ARFGEF2):c.2686-9C>T	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128435	NM_006420.3(ARFGEF2):c.2815-7G>A	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128436	NM_006420.3(ARFGEF2):c.3177G>A (p.Ser1059=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128441	NM_006420.3(ARFGEF2):c.4462A>T (p.Thr1488Ser)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128445	NM_006420.3(ARFGEF2):c.807C>T (p.Asp269=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128446	NM_006420.3(ARFGEF2):c.811C>G (p.Pro271Ala)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1436986	NM_006420.3(ARFGEF2):c.3129G>T (p.Leu1043Phe)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210228	NM_006420.3(ARFGEF2):c.1888G>A (p.Val630Ile)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210231	NM_006420.3(ARFGEF2):c.2253A>G (p.Ala751=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210234	NM_006420.3(ARFGEF2):c.3177G>T (p.Ser1059=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210235	NM_006420.3(ARFGEF2):c.3275G>A (p.Arg1092His)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210239	NM_006420.3(ARFGEF2):c.3892G>A (p.Gly1298Ser)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
210241	NM_006420.3(ARFGEF2):c.4332G>A (p.Ala1444=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338683	NM_006420.3(ARFGEF2):c.1030A>C (p.Arg344=)	ARFGEF2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
ARFGEF2	Strong	Autosomal recessive	periventricular heterotopia with microcephaly, autosomal recessive	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ARFGEF2	Orphanet:98892	Periventricular nodular heterotopia

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
ARFGEF2	HGNC:15853	ENSG00000124198	Q9Y6D5	Brefeldin A-inhibited guanine nucleotide-exchange protein 2	gencc,clinvar
IRS1	HGNC:6125	ENSG00000169047	P35568	Insulin receptor substrate 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ARFGEF2	Brefeldin A-inhibited guanine nucleotide-exchange protein 2	Promotes guanine-nucleotide exchange on ARF1 and ARF3 and to a lower extent on ARF5 and ARF6.
IRS1	Insulin receptor substrate 1	Signaling adapter protein that participates in the signal transduction from two prominent receptor tyrosine kinases, insulin receptor/INSR and insulin-like growth factor I receptor/IGF1R.

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ARFGEF2	Other/Unknown	no		Sec7_dom, ARM-like, Mon2/Sec7/BIG1-like_HDS
IRS1	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf

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
cartilage tissue	1
jejunal mucosa	1
parotid gland	1
endometrium epithelium	1
skeletal muscle tissue of rectus abdominis	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ARFGEF2	289	ubiquitous	marker	cartilage tissue, jejunal mucosa, parotid gland
IRS1	293	ubiquitous	marker	endometrium epithelium, skeletal muscle tissue of rectus abdominis, tibia

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IRS1	4,337
ARFGEF2	2,022

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
IRS1	P35568	8
ARFGEF2	Q9Y6D5	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 42. 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
IRS activation	1	1142.0×	0.007	IRS1
Activated NTRK3 signals through PI3K	1	951.7×	0.007	IRS1
SOS-mediated signalling	1	713.8×	0.007	IRS1
IGF1R signaling cascade	1	713.8×	0.007	IRS1
PI3K/AKT activation	1	634.4×	0.007	IRS1
Signaling by NTRK3 (TRKC)	1	571.0×	0.007	IRS1
IRS-mediated signalling	1	519.1×	0.007	IRS1
IRS-related events triggered by IGF1R	1	519.1×	0.007	IRS1
Signaling by Leptin	1	519.1×	0.007	IRS1
Signal attenuation	1	519.1×	0.007	IRS1
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)	1	475.8×	0.007	IRS1
Signaling by Insulin receptor	1	439.2×	0.007	IRS1
Signaling by LTK	1	439.2×	0.007	IRS1
Insulin receptor signalling cascade	1	335.9×	0.009	IRS1
Signaling by ALK	1	285.5×	0.010	IRS1
Growth hormone receptor signaling	1	237.9×	0.011	IRS1
PI3K/AKT Signaling in Cancer	1	184.2×	0.013	IRS1
Interleukin-7 signaling	1	158.6×	0.013	IRS1
Chaperonin-mediated protein folding	1	150.3×	0.013	ARFGEF2
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.013	ARFGEF2
Negative regulation of the PI3K/AKT network	1	139.3×	0.013	IRS1
PI3K Cascade	1	135.9×	0.013	IRS1
Signaling by ALK in cancer	1	135.9×	0.013	IRS1
Protein folding	1	129.8×	0.013	ARFGEF2
Signaling by NTRK1 (TRKA)	1	98.5×	0.017	IRS1
Signaling by NTRKs	1	90.6×	0.018	IRS1
Signaling by ALK fusions and activated point mutants	1	75.1×	0.021	IRS1
MAPK1/MAPK3 signaling	1	65.6×	0.023	IRS1
Constitutive Signaling by Aberrant PI3K in Cancer	1	63.4×	0.023	IRS1
MAPK family signaling cascades	1	51.4×	0.027	IRS1

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
endomembrane system organization	1	4213.0×	0.007	ARFGEF2
positive regulation of glucose metabolic process	1	1203.7×	0.009	IRS1
positive regulation of fatty acid beta-oxidation	1	766.0×	0.009	IRS1
receptor recycling	1	648.1×	0.009	ARFGEF2
positive regulation of glycogen biosynthetic process	1	495.6×	0.009	IRS1
regulation of ARF protein signal transduction	1	443.5×	0.009	ARFGEF2
positive regulation of insulin receptor signaling pathway	1	421.3×	0.009	IRS1
cellular response to fatty acid	1	351.1×	0.010	IRS1
Golgi to plasma membrane transport	1	280.9×	0.010	ARFGEF2
negative regulation of insulin secretion	1	247.8×	0.010	IRS1
insulin-like growth factor receptor signaling pathway	1	247.8×	0.010	IRS1
positive regulation of D-glucose import across plasma membrane	1	227.7×	0.010	IRS1
endosome organization	1	187.2×	0.011	ARFGEF2
negative regulation of insulin receptor signaling pathway	1	187.2×	0.011	IRS1
response to insulin	1	115.4×	0.016	IRS1
insulin receptor signaling pathway	1	110.9×	0.016	IRS1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	105.3×	0.016	IRS1
cellular response to insulin stimulus	1	85.1×	0.018	IRS1
positive regulation of tumor necrosis factor production	1	76.6×	0.018	ARFGEF2
exocytosis	1	75.9×	0.018	ARFGEF2
cytokine-mediated signaling pathway	1	65.3×	0.019	IRS1
glucose homeostasis	1	65.3×	0.019	IRS1
vesicle-mediated transport	1	48.1×	0.025	ARFGEF2
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.030	IRS1
protein transport	1	21.9×	0.050	ARFGEF2
intracellular signal transduction	1	19.1×	0.056	ARFGEF2
positive regulation of cell population proliferation	1	16.8×	0.061	IRS1
signal transduction	1	8.0×	0.121	IRS1

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
ARFGEF2	0	0
IRS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
IRS1	2	Binding:2
ARFGEF2	1	Binding:1

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	ARFGEF2, IRS1

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)
ARFGEF2	1	—
IRS1	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.