Megalencephaly

Summary

Megalencephaly (MONDO:0016608) is a disease with 2 cohort genes and 1 clinical trial. Molecularly, MTOR E1799K confers sensitivity to Everolimus in Megalencephaly (CIViC Level D).

At a glance

• Cohort genes: 2
• ClinVar variants: 1
• Phenotypes (HPO): 16
• Clinical trials: 1
• Precision-medicine evidence (CIViC): 1 subtype–drug association

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000235	Abnormality of the fontanelles or cranial sutures	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000268	Dolichocephaly	Very frequent (80-99%)
HP:0000269	Prominent occiput	Very frequent (80-99%)
HP:0000307	Pointed chin	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0000490	Deeply set eye	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001956	Truncal obesity	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0000040	Long penis	Frequent (30-79%)
HP:0000053	Macroorchidism	Frequent (30-79%)
HP:0001631	Atrial septal defect	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly
Mondo ID	MONDO:0016608
MeSH	D058627
Orphanet	2477
ICD-10-CM	Q04.5
ICD-11	368780653
SNOMED CT	9740002
UMLS	C0221355
MedGen	65141
GARD	0016601
MedDRA	10050183
Is cancer (heuristic)	no

Also known as: macroencephaly · megalencephaly · megalencephaly (disease)

Data availability: 1 ClinVar variant · 1 HPO phenotype.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (70): leukoencephalopathy, megalencephalic, encephalopathy, acute, infection-induced, diabetic encephalopathy, complex cortical dysplasia with other brain malformations, hydrocephalus, brain compression, cerebral sarcoidosis, hepatic encephalopathy, visual pathway disorder, central nervous system origin vertigo, cerebellar disorder, cerebritis, olfactory nerve disorder, thalamic disorder, pituitary gland disorder, disorder of optic chiasm, basal ganglia disorder, epilepsy, mental disorder, central nervous system cyst, migraine disorder, multiple sclerosis, prion disease, carbon monoxide-induced delayed encephalopathy, cerebral malaria, akinetic mutism, bulbar polio, Reye syndrome, brain edema, encephalomalacia, intracranial hypertension, intracranial hypotension, Wernicke encephalopathy, encephalopathy, recurrent, of childhood, XK aprosencephaly, progressive bulbar palsy, cerebrovascular disorder, glycine encephalopathy, autosomal recessive frontotemporal pachygyria, occipital pachygyria and polymicrogyria, insomnia, narcolepsy-cataplexy syndrome, meningoencephalocele, cerebral cortical dysplasia, encephaloclastic disorder, bilirubin encephalopathy, autoimmune encephalopathy with parasomnia and obstructive sleep apnea, narcolepsy without cataplexy, hypothalamic hamartomas with gelastic seizures, encephalitis, cerebral lipidosis with dementia, brain neoplasm, colpocephaly, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cerebral degeneration, acute bilirubin encephalopathy, chronic bilirubin encephalopathy, atelencephaly, aprosencephaly, brain injury, traumatic encephalopathy, cluster headache syndrome, cerebral cortex disorder, midbrain disorder, encephalopathy due to mitochondrial and peroxisomal fission defect, brain malformations with or without urinary tract defects, encephalopathy, acute transient

Subtypes (4): megalencephaly, autosomal dominant, 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 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1683500	NM_000287.4(PEX6):c.1680C>G (p.Pro560=)	PEX6	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MTOR	Orphanet:269001	Isolated focal cortical dysplasia type IIa
MTOR	Orphanet:269008	Isolated focal cortical dysplasia type IIb
MTOR	Orphanet:457485	Macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome
MTOR	Orphanet:99802	Hemimegalencephaly
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	1
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MTOR	HGNC:3942	ENSG00000198793	P42345	Serine/threonine-protein kinase mTOR	civic_evidence
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MTOR	Serine/threonine-protein kinase mTOR	Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.

Protein-family classification

Druggable: 2 · 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	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MTOR	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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
primordial germ cell in gonad	1
right hemisphere of cerebellum	1
body of pancreas	1
mucosa of transverse colon	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MTOR	207	ubiquitous	marker	primordial germ cell in gonad, right hemisphere of cerebellum, cerebellar hemisphere
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MTOR	9,490
PEX6	2,620

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTOR	P42345	70

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX6	Q13608	69.87

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
Dengue virus modulates apoptosis	1	356.9×	0.020	MTOR
Regulation of TP53 Expression and Degradation	1	259.6×	0.020	MTOR
mTORC1-mediated signalling	1	237.9×	0.020	MTOR
Regulation of T cell activation by CD28 family	1	211.5×	0.020	MTOR
Constitutive Signaling by AKT1 E17K in Cancer	1	211.5×	0.020	MTOR
VEGFR2 mediated vascular permeability	1	203.9×	0.020	MTOR
Cellular response to heat stress	1	196.9×	0.020	MTOR
Energy dependent regulation of mTOR by LKB1-AMPK	1	196.9×	0.020	MTOR
CD28 dependent PI3K/Akt signaling	1	196.9×	0.020	MTOR
Co-stimulation by CD28	1	190.3×	0.020	MTOR
PI3K/AKT Signaling in Cancer	1	184.2×	0.020	MTOR
HSF1-dependent transactivation	1	158.6×	0.020	MTOR
Response of endothelial cells to shear stress	1	150.3×	0.020	MTOR
Regulation of TP53 Degradation	1	146.4×	0.020	MTOR
MTOR signalling	1	132.8×	0.020	MTOR
Cellular responses to mechanical stimuli	1	129.8×	0.020	MTOR
PTEN Regulation	1	114.2×	0.021	MTOR
Signaling by VEGF	1	109.8×	0.021	MTOR
Amino acids regulate mTORC1	1	100.2×	0.022	MTOR
Regulation of PTEN gene transcription	1	89.2×	0.023	MTOR
Peroxisomal protein import	1	86.5×	0.023	PEX6
Cellular response to starvation	1	82.8×	0.023	MTOR
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	80.4×	0.023	MTOR
Autophagy	1	74.2×	0.024	MTOR
VEGFA-VEGFR2 Pathway	1	69.6×	0.024	MTOR
Regulation of TP53 Activity	1	66.4×	0.024	MTOR
TP53 Regulates Metabolic Genes	1	64.9×	0.024	MTOR
Macroautophagy	1	57.7×	0.026	MTOR
Intracellular signaling by second messengers	1	45.7×	0.032	MTOR
PIP3 activates AKT signaling	1	33.4×	0.042	MTOR

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
positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process	1	8426.0×	0.005	MTOR
regulation of locomotor rhythm	1	4213.0×	0.005	MTOR
positive regulation of cytoplasmic translational initiation	1	4213.0×	0.005	MTOR
T-helper 1 cell lineage commitment	1	2106.5×	0.005	MTOR
protein import into peroxisome matrix, translocation	1	2106.5×	0.005	PEX6
negative regulation of lysosome organization	1	2106.5×	0.005	MTOR
positive regulation of pentose-phosphate shunt	1	2106.5×	0.005	MTOR
protein unfolding	1	1685.2×	0.005	PEX6
cellular response to methionine	1	1685.2×	0.005	MTOR
positive regulation of wound healing, spreading of epidermal cells	1	1685.2×	0.005	MTOR
‘de novo’ pyrimidine nucleobase biosynthetic process	1	1404.3×	0.005	MTOR
voluntary musculoskeletal movement	1	1404.3×	0.005	MTOR
regulation of lysosome organization	1	1404.3×	0.005	MTOR
protein stabilization	2	66.9×	0.005	MTOR, PEX6
protein import into peroxisome matrix, receptor recycling	1	1203.7×	0.005	PEX6
regulation of membrane permeability	1	1203.7×	0.005	MTOR
cellular response to nutrient	1	1053.2×	0.005	MTOR
heart valve morphogenesis	1	936.2×	0.005	MTOR
protein targeting to peroxisome	1	842.6×	0.005	PEX6
negative regulation of cell size	1	842.6×	0.005	MTOR
positive regulation of myotube differentiation	1	766.0×	0.005	MTOR
TORC2 signaling	1	766.0×	0.005	MTOR
regulation of osteoclast differentiation	1	766.0×	0.005	MTOR
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	1	766.0×	0.005	MTOR
protein import into peroxisome matrix	1	702.2×	0.005	PEX6
cellular response to L-leucine	1	702.2×	0.005	MTOR
cellular response to leucine starvation	1	702.2×	0.005	MTOR
anoikis	1	648.1×	0.005	MTOR
positive regulation of keratinocyte migration	1	648.1×	0.005	MTOR
cellular response to osmotic stress	1	601.9×	0.005	MTOR

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
MTOR	SALMETEROL XINAFOATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MTOR	164	4
PEX6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
MTOR	1,375	Binding:1335, Functional:37, ADMET:2, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PEX6	3.6.4.7	peroxisome-assembly ATPase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MTOR	1,375

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

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)
SALMETEROL XINAFOATE	4	MTOR
IMIPRAMINE	4	MTOR
AMOXAPINE	4	MTOR
IDARUBICIN	4	MTOR
TETRABENAZINE	4	MTOR
TEMSIROLIMUS	4	MTOR
MIFEPRISTONE	4	MTOR
ZIPRASIDONE HYDROCHLORIDE	4	MTOR
PIMOZIDE	4	MTOR
NAFTOPIDIL	4	MTOR
NICLOSAMIDE	4	MTOR
FELODIPINE	4	MTOR
NICARDIPINE	4	MTOR
AZACITIDINE	4	MTOR
TRIFLUPERIDOL	4	MTOR
CYCLOSPORINE	4	MTOR
CLEMASTINE	4	MTOR
TERFENADINE	4	MTOR
FLUOROURACIL	4	MTOR
PANCURONIUM	4	MTOR
EVEROLIMUS	4	MTOR
NIFEDIPINE	4	MTOR
PRAZOSIN	4	MTOR
MAPROTILINE	4	MTOR
DOMPERIDONE	4	MTOR
ALPELISIB	4	MTOR
TACROLIMUS ANHYDROUS	4	MTOR
EBASTINE	4	MTOR
MASOPROCOL	4	MTOR
COPANLISIB	4	MTOR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MTOR
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PEX6
E	Difficult family or no structure, no drug	0

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)
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05563831	Not specified	COMPLETED	National Evaluation of Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 1 predictive associations from 1 curated evidence items.

Molecular subtype	Therapy	Effect	Level	CIViC
MTOR E1799K	Everolimus	Sensitivity/Response	CIViC D	EID9486