Megalencephaly, autosomal dominant

Summary

Megalencephaly, autosomal dominant (MONDO:0007961) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly, autosomal dominant
Mondo ID	MONDO:0007961
OMIM	155350
UMLS	C3805727
MedGen	812057
GARD	0024590
Is cancer (heuristic)	no

Also known as: megalencephaly, autosomal dominant

Data availability: 1 ClinVar variant.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › megalencephaly › megalencephaly, autosomal dominant

Related subtypes (3): macrocephaly/megalencephaly syndrome, autosomal recessive, isolated megalencephaly, bagatelle Cassidy syndrome

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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
376498	NM_006218.4(PIK3CA):c.1030G>A (p.Val344Met)	PIK3CA	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIK3CA	Orphanet:140944	CLOVES syndrome
PIK3CA	Orphanet:144	Lynch syndrome
PIK3CA	Orphanet:168984	CLAPO syndrome
PIK3CA	Orphanet:201	Cowden syndrome
PIK3CA	Orphanet:210159	Adult hepatocellular carcinoma
PIK3CA	Orphanet:221061	Familial cerebral cavernous malformation
PIK3CA	Orphanet:2495	Meningioma
PIK3CA	Orphanet:276280	Hemihyperplasia-multiple lipomatosis syndrome
PIK3CA	Orphanet:295239	Macrodactyly of fingers, unilateral
PIK3CA	Orphanet:295243	Macrodactyly of toes, unilateral
PIK3CA	Orphanet:314662	Segmental progressive overgrowth syndrome with fibroadipose hyperplasia
PIK3CA	Orphanet:60040	Megalencephaly-capillary malformation-polymicrogyria syndrome
PIK3CA	Orphanet:714737	Diffuse capillary malformation with overgrowth
PIK3CA	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
PIK3CA	Orphanet:99802	Hemimegalencephaly

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
PIK3CA	HGNC:8975	ENSG00000121879	P42336	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIK3CA	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides.

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIK3CA	Kinase	yes	2.7.1.137	PI3K_Ras-bd_dom, PI3/4_kinase_cat_dom, PI3K_accessory_dom

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
adrenal tissue	1
calcaneal tendon	1
tendon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIK3CA	284	ubiquitous	marker	calcaneal tendon, adrenal tissue, tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PIK3CA	5,157

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PIK3CA	P42336	135

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. 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
MET activates PI3K/AKT signaling	1	1903.3×	0.004	PIK3CA
Activated NTRK3 signals through PI3K	1	1903.3×	0.004	PIK3CA
Activated NTRK2 signals through PI3K	1	1631.4×	0.004	PIK3CA
Signaling by LTK in cancer	1	1631.4×	0.004	PIK3CA
PI3K/AKT activation	1	1268.9×	0.004	PIK3CA
IRS-mediated signalling	1	1038.2×	0.004	PIK3CA
PI3K events in ERBB4 signaling	1	1038.2×	0.004	PIK3CA
Co-stimulation by ICOS	1	1038.2×	0.004	PIK3CA
Signaling by FGFR4 in disease	1	951.7×	0.004	PIK3CA
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	951.7×	0.004	PIK3CA
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	878.5×	0.004	PIK3CA
Signaling by PDGFRA extracellular domain mutants	1	878.5×	0.004	PIK3CA
Signaling by LTK	1	878.5×	0.004	PIK3CA
Signaling by FLT3 ITD and TKD mutants	1	761.3×	0.004	PIK3CA
Constitutive Signaling by EGFRvIII	1	713.8×	0.004	PIK3CA
PI3K events in ERBB2 signaling	1	671.8×	0.004	PIK3CA
Signaling by ERBB2 ECD mutants	1	671.8×	0.004	PIK3CA
GAB1 signalosome	1	634.4×	0.004	PIK3CA
Signaling by cytosolic FGFR1 fusion mutants	1	634.4×	0.004	PIK3CA
PI-3K cascade:FGFR3	1	634.4×	0.004	PIK3CA
Tie2 Signaling	1	601.0×	0.004	PIK3CA
Role of LAT2/NTAL/LAB on calcium mobilization	1	601.0×	0.004	PIK3CA
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	1	571.0×	0.004	PIK3CA
Signaling by ALK	1	571.0×	0.004	PIK3CA
PI-3K cascade:FGFR4	1	571.0×	0.004	PIK3CA
Signaling by FLT3 fusion proteins	1	571.0×	0.004	PIK3CA
PI-3K cascade:FGFR1	1	519.1×	0.004	PIK3CA
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	1	519.1×	0.004	PIK3CA
PI-3K cascade:FGFR2	1	496.5×	0.004	PIK3CA
Signaling by FGFR3 in disease	1	496.5×	0.004	PIK3CA

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
response to muscle inactivity	1	16852.0×	0.001	PIK3CA
response to butyrate	1	16852.0×	0.001	PIK3CA
response to L-leucine	1	5617.3×	0.002	PIK3CA
cellular response to hydrostatic pressure	1	5617.3×	0.002	PIK3CA
negative regulation of actin filament depolymerization	1	2808.7×	0.002	PIK3CA
regulation of cellular respiration	1	2808.7×	0.002	PIK3CA
regulation of actin filament organization	1	2407.4×	0.002	PIK3CA
autosome genomic imprinting	1	2407.4×	0.002	PIK3CA
negative regulation of fibroblast apoptotic process	1	2407.4×	0.002	PIK3CA
cardiac muscle cell contraction	1	1685.2×	0.002	PIK3CA
positive regulation of protein localization to membrane	1	1685.2×	0.002	PIK3CA
TORC2 signaling	1	1532.0×	0.002	PIK3CA
phosphatidylinositol-3-phosphate biosynthetic process	1	1296.3×	0.002	PIK3CA
anoikis	1	1296.3×	0.002	PIK3CA
relaxation of cardiac muscle	1	1296.3×	0.002	PIK3CA
response to dexamethasone	1	1203.7×	0.002	PIK3CA
vasculature development	1	1123.5×	0.002	PIK3CA
negative regulation of macroautophagy	1	1123.5×	0.002	PIK3CA
vascular endothelial growth factor signaling pathway	1	1053.2×	0.002	PIK3CA
negative regulation of anoikis	1	887.0×	0.003	PIK3CA
response to muscle stretch	1	766.0×	0.003	PIK3CA
phosphatidylinositol-mediated signaling	1	702.2×	0.003	PIK3CA
regulation of multicellular organism growth	1	648.1×	0.003	PIK3CA
positive regulation of lamellipodium assembly	1	601.9×	0.003	PIK3CA
positive regulation of TOR signaling	1	495.6×	0.004	PIK3CA
insulin-like growth factor receptor signaling pathway	1	495.6×	0.004	PIK3CA
phosphatidylinositol phosphate biosynthetic process	1	481.5×	0.004	PIK3CA
endothelial cell migration	1	411.0×	0.004	PIK3CA
cardiac muscle contraction	1	401.2×	0.004	PIK3CA
adipose tissue development	1	401.2×	0.004	PIK3CA

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PIK3CA	IDELALISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PIK3CA	67	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA
ZSTK-474	2	PIK3CA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PIK3CA	2,034	Binding:2009, ADMET:19, Toxicity:4, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PIK3CA	2.7.1.137, 2.7.1.153, 2.7.11.1	phosphatidylinositol 3-kinase, phosphatidylinositol-4,5-bisphosphate 3-kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PIK3CA	2,034

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

30 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.

Compound	Max phase	Cohort target (bioactivity)
IDELALISIB	4	PIK3CA
ALPELISIB	4	PIK3CA
DUVELISIB	4	PIK3CA
COPANLISIB	4	PIK3CA
FEDRATINIB	4	PIK3CA
ROMIDEPSIN	4	PIK3CA
COPANLISIB HYDROCHLORIDE	4	PIK3CA
LENIOLISIB	4	PIK3CA
BELINOSTAT	4	PIK3CA
INAVOLISIB	4	PIK3CA
SUNITINIB	4	PIK3CA
DASATINIB	4	PIK3CA
CRIZOTINIB	4	PIK3CA
MIDOSTAURIN	4	PIK3CA
DACTOLISIB	3	PIK3CA
BUPARLISIB	3	PIK3CA
RESVERATROL	3	PIK3CA
IPATASERTIB	3	PIK3CA
TASELISIB	3	PIK3CA
EPIGALOCATECHIN GALLATE	3	PIK3CA
GEDATOLISIB	3	PIK3CA
LESTAURTINIB	3	PIK3CA
OMIPALISIB	2	PIK3CA
VISTUSERTIB	2	PIK3CA
FIMEPINOSTAT	2	PIK3CA
EGANELISIB	2	PIK3CA
BERZOSERTIB	2	PIK3CA
BIMIRALISIB	2	PIK3CA
PICTILISIB	2	PIK3CA
ZSTK-474	2	PIK3CA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PIK3CA
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	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.