Bilateral frontoparietal polymicrogyria

Summary

Bilateral frontoparietal polymicrogyria (MONDO:0011738) is a disease caused by ADGRG1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: ADGRG1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 302
• Phenotypes (HPO): 24

Clinical features

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0002119	Ventriculomegaly	Very frequent (80-99%)
HP:0002539	Cortical dysplasia	Very frequent (80-99%)
HP:0007033	Cerebellar dysplasia	Very frequent (80-99%)
HP:0007266	Cerebral dysmyelination	Very frequent (80-99%)
HP:0000565	Esotropia	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001317	Abnormal cerebellum morphology	Frequent (30-79%)
HP:0001320	Cerebellar vermis hypoplasia	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0002463	Language impairment	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012110	Hypoplasia of the pons	Frequent (30-79%)
HP:0025190	Bilateral tonic-clonic seizure with generalized onset	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002365	Hypoplasia of the brainstem	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0011147	Typical absence seizure	Occasional (5-29%)
HP:0040194	Increased head circumference	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	bilateral frontoparietal polymicrogyria
Mondo ID	MONDO:0011738
MeSH	C564652
OMIM	606854
Orphanet	101070
DOID	DOID:0080922
ICD-11	1119484699
NCIT	C148367
UMLS	C1847352
MedGen	376107
GARD	0010784
Is cancer (heuristic)	no

Also known as: BFPP · bilateral frontoparietal polymicrogyria · polymicrogyria, bilateral frontoparietal

Data availability: 302 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › polymicrogyria › bilateral polymicrogyria › bilateral frontoparietal polymicrogyria

Related subtypes (4): bilateral parasagittal parieto-occipital polymicrogyria, bilateral generalized polymicrogyria, bilateral frontal polymicrogyria, bilateral perisylvian polymicrogyria

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

302 retrieved; paginated sample, class counts are floors:

111 uncertain significance, 44 conflicting classifications of pathogenicity, 31 likely benign, 31 benign, 31 likely pathogenic, 26 pathogenic/likely pathogenic, 17 pathogenic, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1075265	NM_201525.4(ADGRG1):c.860_861del (p.Arg287fs)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127079	NM_201525.4(ADGRG1):c.-36+10587_-36+10601del	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1357876	NM_201525.4(ADGRG1):c.1384del (p.Ala461_Leu462insTer)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1369485	NM_201525.4(ADGRG1):c.1486C>T (p.Arg496Ter)	ADGRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1438127	NM_201525.4(ADGRG1):c.562C>T (p.Gln188Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1443377	NM_201525.4(ADGRG1):c.1933+2del	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451570	NM_201525.4(ADGRG1):c.531C>A (p.Cys177Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158618	NM_201525.4(ADGRG1):c.1408C>T (p.Arg470Ter)	ADGRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
158621	NM_201525.4(ADGRG1):c.1515T>G (p.Tyr505Ter)	ADGRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
158627	NM_201525.4(ADGRG1):c.1952G>A (p.Trp651Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158628	NM_201525.4(ADGRG1):c.265C>T (p.His89Tyr)	ADGRG1	Pathogenic	criteria provided, single submitter
158629	NM_201525.4(ADGRG1):c.286C>T (p.Arg96Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
158634	NM_201525.4(ADGRG1):c.620+1G>A	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694450	NM_201525.4(ADGRG1):c.580C>T (p.Gln194Ter)	ADGRG1	Pathogenic	criteria provided, single submitter
189231	NM_201525.4(ADGRG1):c.10C>T (p.Gln4Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2016424	NM_201525.4(ADGRG1):c.1158_1162del (p.Val387fs)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2019888	NM_201525.4(ADGRG1):c.206_209dup (p.Phe71fs)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2025254	NM_201525.4(ADGRG1):c.1131C>A (p.Cys377Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2087510	NM_201525.4(ADGRG1):c.1012C>T (p.Gln338Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
211093	NM_201525.4(ADGRG1):c.1216del (p.Leu406fs)	ADGRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
211096	NM_201525.4(ADGRG1):c.944_945dup (p.Val316fs)	ADGRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2573550	NM_201525.4(ADGRG1):c.1457G>A (p.Trp486Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2579668	NM_201525.4(ADGRG1):c.209C>T (p.Pro70Leu)	ADGRG1	Pathogenic	no assertion criteria provided
2627974	NM_201525.4(ADGRG1):c.429G>A (p.Trp143Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2962815	NM_201525.4(ADGRG1):c.532_553del (p.Glu178fs)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2983670	NM_201525.4(ADGRG1):c.1933+1G>T	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3362665	NM_201525.4(ADGRG1):c.781G>T (p.Glu261Ter)	ADGRG1	Pathogenic	criteria provided, single submitter
3638695	NM_201525.4(ADGRG1):c.1281C>A (p.Cys427Ter)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372729	NM_201525.4(ADGRG1):c.671del (p.Asp224fs)	ADGRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3775176	NM_201525.4(ADGRG1):c.721C>T (p.Gln241Ter)	ADGRG1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
ADGRG1	Definitive	Autosomal recessive	bilateral frontoparietal polymicrogyria	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADGRG1	Orphanet:101070	Bilateral frontoparietal polymicrogyria
ADGRG1	Orphanet:98889	Bilateral perisylvian polymicrogyria

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
ADGRG1	HGNC:4512	ENSG00000205336	Q9Y653	Adhesion G-protein coupled receptor G1	gencc,clinvar
DENND5A	HGNC:19344	ENSG00000184014	Q6IQ26	DENN domain-containing protein 5A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADGRG1	Adhesion G-protein coupled receptor G1	Adhesion G-protein coupled receptor (aGPCR) for steroid hormone 17alpha-hydroxypregnenolone (17-OH), which is involved in cell adhesion and cell-cell interactions.
DENND5A	DENN domain-containing protein 5A	Guanine nucleotide exchange factor (GEF) which may activate RAB6A and RAB39A and/or RAB39B.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADGRG1	GPCR	yes		GPS, GPCR_2_secretin-like, GPR1/GPR3/GPR5
DENND5A	Other/Unknown	no		PLAT/LH2_dom, cDENN_dom, Run_dom

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
ganglionic eminence	1
granulocyte	1
ventricular zone	1
C1 segment of cervical spinal cord	1
corpus callosum	1
medial globus pallidus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADGRG1	284	ubiquitous	marker	granulocyte, ganglionic eminence, ventricular zone
DENND5A	282	ubiquitous	marker	corpus callosum, medial globus pallidus, C1 segment of cervical spinal cord

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ADGRG1	1,541
DENND5A	1,033

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ADGRG1	Q9Y653	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DENND5A	Q6IQ26	77.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 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
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	DENND5A

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
cerebral cortex radial glia-guided migration	1	2106.5×	0.005	ADGRG1
cerebral cortex regionalization	1	1203.7×	0.005	ADGRG1
regulation of platelet aggregation	1	1203.7×	0.005	ADGRG1
Rho-activating G protein-coupled receptor signaling pathway	1	1203.7×	0.005	ADGRG1
negative regulation of neuron migration	1	702.2×	0.007	ADGRG1
layer formation in cerebral cortex	1	561.7×	0.007	ADGRG1
positive regulation of vascular endothelial growth factor signaling pathway	1	561.7×	0.007	ADGRG1
negative regulation of ferroptosis	1	401.2×	0.007	ADGRG1
seminiferous tubule development	1	383.0×	0.007	ADGRG1
positive regulation of neural precursor cell proliferation	1	383.0×	0.007	ADGRG1
neural precursor cell proliferation	1	337.0×	0.007	ADGRG1
positive regulation of Rho protein signal transduction	1	290.6×	0.007	ADGRG1
hematopoietic stem cell homeostasis	1	280.9×	0.007	ADGRG1
positive regulation of cell adhesion	1	135.9×	0.014	ADGRG1
Rho protein signal transduction	1	123.9×	0.014	ADGRG1
negative regulation of neuron projection development	1	118.7×	0.014	DENND5A
retrograde transport, endosome to Golgi	1	102.8×	0.015	DENND5A
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.022	ADGRG1
brain development	1	39.8×	0.034	ADGRG1
cell-cell signaling	1	34.8×	0.036	ADGRG1
cell surface receptor signaling pathway	1	32.0×	0.036	ADGRG1
angiogenesis	1	31.2×	0.036	ADGRG1
cell migration	1	30.8×	0.036	ADGRG1
negative regulation of cell population proliferation	1	21.1×	0.051	ADGRG1
cell adhesion	1	18.7×	0.054	ADGRG1
G protein-coupled receptor signaling pathway	1	18.1×	0.054	ADGRG1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADGRG1	0	0
DENND5A	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
ADGRG1	3	Binding:3

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	1	ADGRG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DENND5A

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)
ADGRG1	3	—
DENND5A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.