Complex neurodevelopmental disorder with or without congenital anomalies

Summary

Complex neurodevelopmental disorder with or without congenital anomalies (MONDO:0100465) is a disease caused by MYH10 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: MYH10 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex neurodevelopmental disorder with or without congenital anomalies
Mondo ID	MONDO:0100465
GARD	0027066
Is cancer (heuristic)	no

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

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › complex neurodevelopmental disorder › complex neurodevelopmental disorder with or without congenital anomalies

Related subtypes (14): pervasive developmental disorder, Prader-Willi syndrome, intellectual disability, autosomal dominant 29, neurodevelopmental disorder with language impairment and behavioral abnormalities, neurodevelopmental disorder with severe motor impairment and absent language, X-linked complex neurodevelopmental disorder, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder with motor features, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, developmental and epileptic encephalopathy, syndromic complex neurodevelopmental disorder, DEAF1-associated neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, GRIN-related complex neurodevelopmental disorder

Subtypes (2): SOX11-related complex neurodevelopmental disorder with or without congenital anomalies, MYH10-related neurodevelopmental disorder with congenital anomalies

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

4 retrieved; paginated sample, class counts are floors:

2 uncertain significance, 1 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
805981	NM_001260.3(CDK8):c.185C>T (p.Ser62Leu)	CDK8	Pathogenic	criteria provided, multiple submitters, no conflicts
4072317	NM_001256012.3(MYH10):c.4681C>T (p.Leu1561Phe)	MYH10	Uncertain significance	criteria provided, single submitter
2960977	NM_001375524.1(TRRAP):c.6322C>G (p.Leu2108Val)	TRRAP	Uncertain significance	criteria provided, multiple submitters, no conflicts
2053328	NM_001375524.1(TRRAP):c.3592-6T>A	TRRAP	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
MYH10	Definitive	Autosomal dominant	complex neurodevelopmental disorder with or without congenital anomalies	4
MED16	Strong	Autosomal recessive	complex neurodevelopmental disorder	2
VPS52	Moderate	Autosomal recessive	complex neurodevelopmental disorder with or without congenital anomalies

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TRRAP	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CDK8	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYH10	HGNC:7568	ENSG00000133026	P35580	Myosin-10	gencc,clinvar
VPS52	HGNC:10518	ENSG00000223501	Q8N1B4	Vacuolar protein sorting-associated protein 52 homolog	gencc
MED16	HGNC:17556	ENSG00000175221	Q9Y2X0	Mediator of RNA polymerase II transcription subunit 16	gencc
TRRAP	HGNC:12347	ENSG00000196367	Q9Y4A5	Transformation/transcription domain-associated protein	clinvar
CDK8	HGNC:1779	ENSG00000132964	P49336	Cyclin-dependent kinase 8	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH10	Myosin-10	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
VPS52	Vacuolar protein sorting-associated protein 52 homolog	Acts as a component of the GARP complex that is involved in retrograde transport from early and late endosomes to the trans-Golgi network (TGN).
MED16	Mediator of RNA polymerase II transcription subunit 16	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TRRAP	Transformation/transcription domain-associated protein	Adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which gives a specific tag for epigenetic transcription activation.
CDK8	Cyclin-dependent kinase 8	Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.4

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	2	11.1×	0.036
Scaffold/PPI	2	6.9×	0.045
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH10	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
VPS52	Other/Unknown	no		Vps52, Vps52_CC, Vps52_C
MED16	Scaffold/PPI	no		WD40_rpt, Quinoprot_gluc/sorb_DH_b-prop, WD40/YVTN_repeat-like_dom_sf
TRRAP	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
CDK8	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right uterine tube	2
blood vessel layer	1
right coronary artery	1
saphenous vein	1
pituitary gland	1
right lobe of thyroid gland	1
lower esophagus mucosa	1
mucosa of transverse colon	1
ganglionic eminence	1
sural nerve	1
ventricular zone	1
adrenal tissue	1
buccal mucosa cell	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH10	300	ubiquitous	marker	blood vessel layer, saphenous vein, right coronary artery
VPS52	134	ubiquitous	marker	right lobe of thyroid gland, right uterine tube, pituitary gland
MED16	167	ubiquitous	marker	lower esophagus mucosa, mucosa of transverse colon, right uterine tube
TRRAP	241	ubiquitous	marker	ventricular zone, sural nerve, ganglionic eminence
CDK8	289	ubiquitous	yes	adrenal tissue, buccal mucosa cell, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRRAP	4,847
MYH10	3,368
CDK8	2,827
VPS52	2,108
MED16	1,631

Intra-cohort edges

A	B	Sources
CDK8	MED16	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDK8	P49336	36
MED16	Q9Y2X0	10
TRRAP	Q9Y4A5	9
MYH10	P35580	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
VPS52	Q8N1B4	86.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	2	86.2×	0.004	MED16, CDK8
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	2	78.8×	0.004	MED16, CDK8
Respiratory Syncytial Virus Infection Pathway	2	78.8×	0.004	MED16, CDK8
RSV-host interactions	2	62.6×	0.004	MED16, CDK8
Adipogenesis	2	62.6×	0.004	MED16, CDK8
Epigenetic regulation by WDR5-containing histone modifying complexes	2	61.7×	0.004	MED16, CDK8
Regulation of lipid metabolism by PPARalpha	2	56.4×	0.004	MED16, CDK8
Transcriptional regulation of white adipocyte differentiation	2	51.9×	0.004	MED16, CDK8
PPARA activates gene expression	2	37.8×	0.006	MED16, CDK8
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	2	33.1×	0.007	MED16, CDK8
Epigenetic regulation of gene expression	2	28.6×	0.009	MED16, CDK8
Developmental Biology	3	8.7×	0.013	MYH10, MED16, CDK8
Sema4D in semaphorin signaling	1	134.3×	0.027	MYH10
RHO GTPases activate CIT	1	120.2×	0.027	MYH10
RHO GTPases Activate ROCKs	1	120.2×	0.027	MYH10
Sema4D induced cell migration and growth-cone collapse	1	114.2×	0.027	MYH10
RHO GTPases activate PAKs	1	108.8×	0.027	MYH10
Metabolism of lipids	2	12.6×	0.027	MED16, CDK8
Viral Infection Pathways	2	12.3×	0.027	MED16, CDK8
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	81.6×	0.028	CDK8
Signaling by NOTCH1 in Cancer	1	81.6×	0.028	CDK8
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	81.6×	0.028	CDK8
Semaphorin interactions	1	78.8×	0.028	MYH10
EPHA-mediated growth cone collapse	1	76.1×	0.028	MYH10
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	73.7×	0.028	CDK8
Signaling by NOTCH1	1	71.4×	0.028	CDK8
Infectious disease	2	9.9×	0.029	MED16, CDK8
RHO GTPases activate PKNs	1	63.4×	0.029	MYH10
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	61.7×	0.029	CDK8
RNA Polymerase II Transcription	2	9.0×	0.031	MED16, CDK8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic ectodermal digestive tract development	1	3370.4×	0.015	VPS52
fourth ventricle development	1	1685.2×	0.015	MYH10
ectodermal cell differentiation	1	842.6×	0.015	VPS52
third ventricle development	1	674.1×	0.015	MYH10
vesicle-mediated cholesterol transport	1	561.7×	0.015	VPS52
Golgi to vacuole transport	1	374.5×	0.015	VPS52
postsynaptic actin cytoskeleton organization	1	374.5×	0.015	MYH10
cardiac septum development	1	337.0×	0.015	MYH10
substrate-dependent cell migration, cell extension	1	306.4×	0.015	MYH10
cerebellar Purkinje cell layer development	1	306.4×	0.015	MYH10
ventricular cardiac muscle cell development	1	306.4×	0.015	MYH10
lateral ventricle development	1	259.3×	0.015	MYH10
cardiac myofibril assembly	1	259.3×	0.015	MYH10
adult heart development	1	240.7×	0.015	MYH10
actin filament-based movement	1	160.5×	0.019	MYH10
nuclear migration	1	146.5×	0.019	MYH10
lysosomal transport	1	140.4×	0.019	VPS52
DNA repair-dependent chromatin remodeling	1	134.8×	0.019	TRRAP
coronary vasculature development	1	124.8×	0.019	MYH10
plasma membrane repair	1	116.2×	0.019	MYH10
cardiac muscle cell proliferation	1	116.2×	0.019	MYH10
regulation of double-strand break repair	1	116.2×	0.019	TRRAP
actomyosin structure organization	1	112.3×	0.019	MYH10
aorta development	1	112.3×	0.019	MYH10
positive regulation of DNA-templated transcription	2	11.2×	0.025	TRRAP, MED16
symbiont entry into host cell	1	80.2×	0.025	MYH10
positive regulation of double-strand break repair via homologous recombination	1	76.6×	0.025	TRRAP
protein targeting	1	73.3×	0.025	VPS52
positive regulation of protein secretion	1	68.8×	0.026	MYH10
neuromuscular process controlling balance	1	66.1×	0.026	MYH10

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 5 evidence-associated genes (80%) 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
MYH10	QUIZARTINIB
CDK8	SORAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK8	23	4
MYH10	2	4
MED16	1	2
VPS52	0	0
TRRAP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
QUIZARTINIB	4	CDK8, MYH10
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
R-406	2	MYH10
MOLIBRESIB	2	MED16
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK8	509	Binding:499, Functional:10
MED16	6	Binding:6
MYH10	3	Binding:3
TRRAP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDK8	2.7.11.22, 2.7.11.23	cyclin-dependent kinase, [RNA-polymerase]-subunit kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CDK8	509

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

25 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)
QUIZARTINIB	4	CDK8, MYH10
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
R-406	2	MYH10
MOLIBRESIB	2	MED16
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MYH10, CDK8
B	Phased (≥1) drug, not yet approved	1	MED16
C	Druggable family + PDB, no drug	1	TRRAP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	VPS52

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)
VPS52	0	—
TRRAP	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.