Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

Summary

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 (MONDO:0014407) is a disease caused by AKT3 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: AKT3 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 123

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2
Mondo ID	MONDO:0014407
OMIM	615937
UMLS	C4014738
MedGen	863175
GARD	0018078
Is cancer (heuristic)	no

Also known as: AKT3 megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2 · megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome type 2 · megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome caused by mutation in AKT3 · MPPH2

Data availability: 123 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › hydrocephalus › megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome › megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2

Related subtypes (2): megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1, megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 3

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

123 retrieved; paginated sample, class counts are floors:

53 likely benign, 33 uncertain significance, 11 benign, 9 conflicting classifications of pathogenicity, 7 pathogenic, 4 likely pathogenic, 3 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1320062	NM_005465.7(AKT3):c.538A>G (p.Lys180Glu)	AKT3	Pathogenic	criteria provided, single submitter
2425356	NC_000001.10:g.(?243652296)(243859038_?)del	AKT3	Pathogenic	criteria provided, single submitter
39814	NM_005465.7(AKT3):c.1393C>T (p.Arg465Trp)	AKT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39815	NM_005465.7(AKT3):c.686A>G (p.Asn229Ser)	AKT3	Pathogenic	criteria provided, single submitter
39816	NM_005465.7(AKT3):c.49G>A (p.Glu17Lys)	AKT3	Pathogenic	reviewed by expert panel
422166	NM_005465.7(AKT3):c.964G>A (p.Asp322Asn)	AKT3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
995385	NM_005465.7(AKT3):c.963T>G (p.Asn321Lys)	AKT3	Pathogenic	no assertion criteria provided
424046	NM_001376.5(DYNC1H1):c.4868G>A (p.Arg1623Gln)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
243062	Single allele	LINC02774	Pathogenic	criteria provided, single submitter
2579289	GRCh38/hg38 1q42.13-44(chr1:230178121-243646135)x1	LOC126806056	Pathogenic	criteria provided, single submitter
1065925	NM_005465.7(AKT3):c.964G>T (p.Asp322Tyr)	AKT3	Likely pathogenic	criteria provided, single submitter
1299320	NM_005465.7(AKT3):c.237G>C (p.Trp79Cys)	AKT3	Likely pathogenic	criteria provided, single submitter
1320279	NM_005465.7(AKT3):c.230T>A (p.Leu77His)	AKT3	Likely pathogenic	no assertion criteria provided
273671	NM_005465.7(AKT3):c.548T>A (p.Val183Asp)	AKT3	Likely pathogenic	criteria provided, single submitter
1281311	NM_005465.7(AKT3):c.16A>G (p.Ile6Val)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1440227	NM_005465.7(AKT3):c.1202G>A (p.Arg401Lys)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1505641	NM_005465.7(AKT3):c.409A>G (p.Thr137Ala)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1518305	NM_005465.7(AKT3):c.685A>C (p.Asn229His)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3711499	NM_005465.7(AKT3):c.324A>T (p.Arg108Ser)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
489265	NM_005465.7(AKT3):c.820-10T>G	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
807366	NM_005465.7(AKT3):c.1330A>G (p.Ile444Val)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
871333	NM_005465.7(AKT3):c.803T>C (p.Val268Ala)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
958474	NM_005465.7(AKT3):c.1397C>T (p.Pro466Leu)	AKT3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342647	NM_005465.7(AKT3):c.47-52492A>G	AKT3	Uncertain significance	criteria provided, single submitter
1347707	NM_005465.7(AKT3):c.948+3A>G	AKT3	Uncertain significance	criteria provided, single submitter
1440421	NC_000001.10:g.(?243663038)(243668656_?)dup	AKT3	Uncertain significance	criteria provided, single submitter
1474549	NM_005465.7(AKT3):c.1251+5G>T	AKT3	Uncertain significance	criteria provided, single submitter
1498287	NM_005465.7(AKT3):c.410C>T (p.Thr137Ile)	AKT3	Uncertain significance	criteria provided, single submitter
2058570	NM_005465.7(AKT3):c.548T>C (p.Val183Ala)	AKT3	Uncertain significance	criteria provided, single submitter
2083338	NM_005465.7(AKT3):c.359G>A (p.Ser120Asn)	AKT3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 5 · 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
AKT3	Strong	Autosomal dominant	megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 2	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AKT3	Orphanet:83473	Megalencephaly-polymicrogyria-postaxial polydactyly-hydrocephalus syndrome
AKT3	Orphanet:99802	Hemimegalencephaly
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AKT3	HGNC:393	ENSG00000117020	Q9Y243	RAC-gamma serine/threonine-protein kinase	gencc,clinvar
CHML	HGNC:1941	ENSG00000203668	P26374	Rab proteins geranylgeranyltransferase component A 2	clinvar
LINC02774	HGNC:27923	ENSG00000226828		long intergenic non-protein coding RNA 2774	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AKT3	RAC-gamma serine/threonine-protein kinase	AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis.
CHML	Rab proteins geranylgeranyltransferase component A 2	Substrate-binding subunit (component A) of the Rab geranylgeranyltransferase (GGTase) complex.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.25

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	6.9×	0.273
Other/Unknown	3	1.3×	0.404

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AKT3	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, PH_domain
CHML	Other/Unknown	no		Rab_escort, GDP_dissociation_inhibitor, FAD/NAD-bd_sf
LINC02774	Other/Unknown	no
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail

Expression context

Cohort genes with no expression data: 0.

3 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	3
ventricular zone	2
calcaneal tendon	1
embryo	1
male germ cell	1
sperm	1
primordial germ cell in gonad	1
superior frontal gyrus	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AKT3	231	ubiquitous	marker	cortical plate, calcaneal tendon, embryo
CHML	251	broad	marker	sperm, cortical plate, male germ cell
LINC02774	101		yes	primordial germ cell in gonad, superior frontal gyrus, ventricular zone
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
AKT3	3,392
CHML	916
LINC02774	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
AKT3	Q9Y243	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CHML	P26374	79.77

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 104. Enrichment computed across 4 evidence-associated genes (3 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 3 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	2	82.8×	0.020	AKT3, CHML
AKT-mediated inactivation of FOXO1A	1	951.7×	0.030	AKT3
Inhibition of TSC complex formation by AKT (PKB)	1	761.3×	0.030	AKT3
G-protein beta:gamma signalling	1	634.4×	0.030	AKT3
RUNX2 regulates genes involved in cell migration	1	475.8×	0.030	AKT3
AKT phosphorylates targets in the nucleus	1	380.7×	0.030	AKT3
Regulation of localization of FOXO transcription factors	1	317.2×	0.030	AKT3
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	292.8×	0.030	AKT3
Downregulation of ERBB2:ERBB3 signaling	1	271.9×	0.030	AKT3
AKT phosphorylates targets in the cytosol	1	271.9×	0.030	AKT3
Regulation of TP53 Activity through Association with Co-factors	1	271.9×	0.030	AKT3
Activation of BAD and translocation to mitochondria	1	253.8×	0.030	AKT3
Regulation of beta-cell development	1	237.9×	0.030	AKT3
Regulation of gene expression in beta cells	1	173.0×	0.030	AKT3
Co-inhibition by CTLA4	1	173.0×	0.030	AKT3
Regulation of TP53 Expression and Degradation	1	173.0×	0.030	AKT3
Activation of BH3-only proteins	1	165.5×	0.030	AKT3
Regulation of TP53 Activity through Acetylation	1	152.3×	0.030	AKT3
G beta:gamma signalling through PI3Kgamma	1	146.4×	0.030	AKT3
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	146.4×	0.030	AKT3
Regulation of T cell activation by CD28 family	1	141.0×	0.030	AKT3
Constitutive Signaling by AKT1 E17K in Cancer	1	141.0×	0.030	AKT3
VEGFR2 mediated vascular permeability	1	135.9×	0.030	AKT3
CD28 dependent PI3K/Akt signaling	1	131.3×	0.030	AKT3
Co-stimulation by CD28	1	126.9×	0.030	AKT3
Downregulation of ERBB2 signaling	1	126.9×	0.030	AKT3
PI3K/AKT Signaling in Cancer	1	122.8×	0.030	AKT3
Rab regulation of trafficking	1	122.8×	0.030	AKT3
Signaling by ERBB2	1	115.3×	0.030	AKT3
FLT3 Signaling	1	115.3×	0.030	AKT3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of metaphase plate congression	1	1123.5×	0.009	DYNC1H1
positive regulation of artery morphogenesis	1	1123.5×	0.009	AKT3
protein geranylgeranylation	1	936.2×	0.009	CHML
establishment of spindle localization	1	936.2×	0.009	DYNC1H1
positive regulation of spindle assembly	1	702.2×	0.009	DYNC1H1
positive regulation of intracellular transport	1	561.7×	0.009	DYNC1H1
retrograde axonal transport	1	510.7×	0.009	DYNC1H1
negative regulation of PERK-mediated unfolded protein response	1	468.1×	0.009	AKT3
positive regulation of cell size	1	432.1×	0.009	AKT3
P-body assembly	1	351.1×	0.009	DYNC1H1
regulation of mitochondrion organization	1	280.9×	0.009	AKT3
regulation of mitotic spindle organization	1	280.9×	0.009	DYNC1H1
positive regulation of vascular endothelial cell proliferation	1	280.9×	0.009	AKT3
nuclear migration	1	244.2×	0.009	DYNC1H1
brain morphogenesis	1	244.2×	0.009	AKT3
positive regulation of cell migration involved in sprouting angiogenesis	1	244.2×	0.009	AKT3
negative regulation of cellular senescence	1	216.1×	0.009	AKT3
stress granule assembly	1	200.6×	0.009	DYNC1H1
positive regulation of TOR signaling	1	165.2×	0.011	AKT3
homeostasis of number of cells within a tissue	1	147.8×	0.011	AKT3
positive regulation of blood vessel endothelial cell migration	1	130.6×	0.012	AKT3
cytoplasmic microtubule organization	1	114.6×	0.013	DYNC1H1
mitotic spindle organization	1	90.6×	0.016	DYNC1H1
positive regulation of endothelial cell proliferation	1	77.0×	0.018	AKT3
insulin receptor signaling pathway	1	73.9×	0.018	AKT3
small GTPase-mediated signal transduction	1	61.1×	0.021	CHML
positive regulation of cold-induced thermogenesis	1	54.5×	0.023	DYNC1H1
positive regulation of angiogenesis	1	38.5×	0.031	AKT3
vesicle-mediated transport	1	32.1×	0.036	CHML
intracellular protein transport	1	21.6×	0.052	CHML

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 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
AKT3	CAPIVASERTIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AKT3	18	4
DYNC1H1	1	2
CHML	0	0
LINC02774	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3
IPATASERTIB	3	AKT3
AFURESERTIB	3	AKT3
ENZASTAURIN	3	AKT3
FASUDIL	3	AKT3
LESTAURTINIB	3	AKT3
RUBOXISTAURIN	3	AKT3
MIRANSERTIB	2	AKT3
MK-2206	2	AKT3
UPROSERTIB	2	AKT3
MOLIBRESIB	2	DYNC1H1
AT-13148	1	AKT3
GSK-690693	1	AKT3
GSK-1070916	1	AKT3
JNJ-26483327	1	AKT3
PF-03758309	1	AKT3
BAY-1125976	1	AKT3
VEVORISERTIB	1	AKT3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AKT3	660	Binding:644, Functional:16
DYNC1H1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AKT3	2.7.11.1	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
AKT3	660

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

19 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)
CAPIVASERTIB	4	AKT3
MIDOSTAURIN	4	AKT3
IPATASERTIB	3	AKT3
AFURESERTIB	3	AKT3
ENZASTAURIN	3	AKT3
FASUDIL	3	AKT3
LESTAURTINIB	3	AKT3
RUBOXISTAURIN	3	AKT3
MIRANSERTIB	2	AKT3
MK-2206	2	AKT3
UPROSERTIB	2	AKT3
MOLIBRESIB	2	DYNC1H1
AT-13148	1	AKT3
GSK-690693	1	AKT3
GSK-1070916	1	AKT3
JNJ-26483327	1	AKT3
PF-03758309	1	AKT3
BAY-1125976	1	AKT3
VEVORISERTIB	1	AKT3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AKT3
B	Phased (≥1) drug, not yet approved	1	DYNC1H1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	CHML, LINC02774

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)
CHML	0	—
LINC02774	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.