Complex neurodevelopmental disorder with motor features

Summary

Complex neurodevelopmental disorder with motor features (MONDO:0100516) is a disease caused by variants in EMC1 and PSMF1, with 5 cohort genes.

At a glance

• Causal genes: EMC1 (GenCC Strong), PSMF1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex neurodevelopmental disorder with motor features
Mondo ID	MONDO:0100516
GARD	0027067
Is cancer (heuristic)	no

Data availability: 8 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 4 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 motor features

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 or without congenital anomalies, 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 (4): complex cortical dysplasia with other brain malformations 5, cerebellar atrophy, visual impairment, and psychomotor retardation;, cerebral palsy, spastic quadriplegic, 3, CACNA1A-related complex neurodevelopmental disorder

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

8 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
3377283	NM_014727.3(KMT2B):c.430C>T (p.Gln144Ter)	KMT2B	Pathogenic	criteria provided, single submitter
4818958	NM_014727.3(KMT2B):c.252G>A (p.Trp84Ter)	KMT2B	Pathogenic	criteria provided, single submitter
2056014	NM_000718.4(CACNA1B):c.5945G>A (p.Arg1982Gln)	CACNA1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3082873	NM_016824.5(ADD3):c.1763C>G (p.Ala588Gly)	ADD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
3082922	NM_016824.5(ADD3):c.776A>T (p.Asp259Val)	ADD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
2058507	NM_000718.4(CACNA1B):c.4667C>T (p.Ala1556Val)	CACNA1B	Uncertain significance	criteria provided, multiple submitters, no conflicts
3764090	NM_014727.3(KMT2B):c.2872G>A (p.Gly958Ser)	KMT2B	Uncertain significance	no assertion criteria provided
3377301	NM_006814.5(PSMF1):c.81T>G (p.His27Gln)	PSMF1	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
EMC1	Strong	Autosomal dominant	complex neurodevelopmental disorder with motor features	7
PSMF1	Strong	Autosomal recessive	complex neurodevelopmental disorder with motor features

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EMC1	Orphanet:480898	Global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome
CACNA1B	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
KMT2B	Orphanet:528084	Non-specific syndromic intellectual disability
KMT2B	Orphanet:589618	Dystonia 28
ADD3	Orphanet:210141	Inherited congenital spastic tetraplegia

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
PSMF1	HGNC:9571	ENSG00000125818	Q92530	Proteasome inhibitor PI31 subunit	gencc,clinvar
EMC1	HGNC:28957	ENSG00000127463	Q8N766	ER membrane protein complex subunit 1	gencc
CACNA1B	HGNC:1389	ENSG00000148408	Q00975	Voltage-dependent N-type calcium channel subunit alpha-1B	clinvar
KMT2B	HGNC:15840	ENSG00000272333	Q9UMN6	Histone-lysine N-methyltransferase 2B	clinvar
ADD3	HGNC:245	ENSG00000148700	Q9UEY8	Gamma-adducin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMF1	Proteasome inhibitor PI31 subunit	Plays an important role in control of proteasome function.
EMC1	ER membrane protein complex subunit 1	Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins.
CACNA1B	Voltage-dependent N-type calcium channel subunit alpha-1B	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
KMT2B	Histone-lysine N-methyltransferase 2B	Histone methyltransferase that catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of ‘Lys-4’ of histone H3 (H3K4) via a non-processive mechanism.
ADD3	Gamma-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Ion channel	1	22.3×	0.176
Scaffold/PPI	1	3.5×	0.515
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMF1	Other/Unknown	no		PI31_Prot_C, PI31_Prot_N, PI31-like
EMC1	Scaffold/PPI	no		Quinoprotein_ADH-like_sf, EMC1_C, WD40/YVTN_repeat-like_dom_sf
CACNA1B	Ion channel	yes		EF_hand_dom, VDCCAlpha1, VDCC_N_a1su
KMT2B	Transcription factor	no		SET_dom, Znf_PHD, Znf_CXXC
ADD3	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf

Expression context

Cohort genes with no expression data: 0.

5 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
left testis	2
male germ cell	1
sperm	1
islet of Langerhans	1
stromal cell of endometrium	1
sural nerve	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
postcentral gyrus	1
lower esophagus mucosa	1
right testis	1
dorsal motor nucleus of vagus nerve	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMF1	302	ubiquitous	marker	sperm, male germ cell, left testis
EMC1	276	ubiquitous	marker	stromal cell of endometrium, islet of Langerhans, sural nerve
CACNA1B	146	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, postcentral gyrus
KMT2B	269	ubiquitous	marker	right testis, left testis, lower esophagus mucosa
ADD3	303	ubiquitous	marker	secondary oocyte, oocyte, dorsal motor nucleus of vagus nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KMT2B	2,639
CACNA1B	2,441
EMC1	2,291
ADD3	1,882
PSMF1	1,553

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EMC1	Q8N766	10
CACNA1B	Q00975	7
KMT2B	Q9UMN6	4
PSMF1	Q92530	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADD3	Q9UEY8	66.83

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Presynaptic depolarization and calcium channel opening	1	237.9×	0.068	CACNA1B
Miscellaneous transport and binding events	1	109.8×	0.068	ADD3
Formation of WDR5-containing histone-modifying complexes	1	66.4×	0.068	KMT2B
RHOF GTPase cycle	1	64.9×	0.068	ADD3
Deactivation of the beta-catenin transactivating complex	1	58.3×	0.068	KMT2B
RHOD GTPase cycle	1	51.0×	0.068	ADD3
Proteasome assembly	1	51.0×	0.068	PSMF1
PKMTs methylate histone lysines	1	40.2×	0.068	KMT2B
Epigenetic regulation by WDR5-containing histone modifying complexes	1	38.6×	0.068	KMT2B
Transcriptional regulation by RUNX1	1	36.6×	0.068	KMT2B
Formation of the beta-catenin:TCF transactivating complex	1	30.1×	0.068	KMT2B
RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function	1	30.1×	0.068	KMT2B
Chromatin organization	1	20.4×	0.086	KMT2B
Transmission across Chemical Synapses	1	19.0×	0.086	CACNA1B
Chromatin modifying enzymes	1	18.1×	0.086	KMT2B
Epigenetic regulation of gene expression	1	17.8×	0.086	KMT2B
RHO GTPase cycle	1	15.0×	0.095	ADD3
Neuronal System	1	11.1×	0.121	CACNA1B
Signaling by Rho GTPases	1	8.6×	0.143	ADD3
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.143	ADD3
Transport of small molecules	1	6.3×	0.178	ADD3
RNA Polymerase II Transcription	1	5.6×	0.189	KMT2B
Gene expression (Transcription)	1	4.5×	0.224	KMT2B
Generic Transcription Pathway	1	3.8×	0.250	KMT2B
Signal Transduction	1	2.5×	0.339	ADD3

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
positive regulation of calcium ion-dependent exocytosis of neurotransmitter	1	1123.5×	0.014	CACNA1B
positive regulation of cytoskeleton organization	1	561.7×	0.014	ADD3
protein insertion into ER membrane by stop-transfer membrane-anchor sequence	1	306.4×	0.014	EMC1
negative regulation of proteasomal protein catabolic process	1	280.9×	0.014	PSMF1
response to amyloid-beta	1	198.3×	0.014	CACNA1B
tail-anchored membrane protein insertion into ER membrane	1	187.2×	0.014	EMC1
barbed-end actin filament capping	1	160.5×	0.014	ADD3
positive regulation of vasoconstriction	1	120.4×	0.016	ADD3
calcium ion import across plasma membrane	1	108.7×	0.016	CACNA1B
modulation of chemical synaptic transmission	1	36.6×	0.042	CACNA1B
methylation	1	34.0×	0.042	KMT2B
chemical synaptic transmission	1	15.5×	0.080	CACNA1B
ubiquitin-dependent protein catabolic process	1	14.8×	0.080	PSMF1
response to xenobiotic stimulus	1	13.8×	0.080	ADD3
proteasome-mediated ubiquitin-dependent protein catabolic process	1	10.4×	0.098	PSMF1
positive regulation of DNA-templated transcription	1	5.6×	0.167	KMT2B

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
CACNA1B	NIFEDIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1B	23	4
PSMF1	0	0
EMC1	0	0
KMT2B	0	0
ADD3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIFEDIPINE	4	CACNA1B
NIMODIPINE	4	CACNA1B
TACRINE	4	CACNA1B
IMIPRAMINE	4	CACNA1B
AMOXAPINE	4	CACNA1B
MAPROTILINE	4	CACNA1B
CLOMIPRAMINE	4	CACNA1B
NORTRIPTYLINE	4	CACNA1B
MIBEFRADIL	4	CACNA1B
ZICONOTIDE	4	CACNA1B
AMITRIPTYLINE	4	CACNA1B
PROMETHAZINE	4	CACNA1B
TRIMIPRAMINE	4	CACNA1B
PROTRIPTYLINE	4	CACNA1B
CYCLOBENZAPRINE	4	CACNA1B
DESIPRAMINE	4	CACNA1B
HESPERIDIN	3	CACNA1B
OPIPRAMOL	3	CACNA1B
CILNIDIPINE	3	CACNA1B
Z160	2	CACNA1B
SELICICLIB	2	CACNA1B
LOMERIZINE	2	CACNA1B
FLUNARIZINE	2	CACNA1B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1B	135	Binding:110, Functional:25
KMT2B	15	Binding:15
EMC1	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1B	135

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

23 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)
NIFEDIPINE	4	CACNA1B
NIMODIPINE	4	CACNA1B
TACRINE	4	CACNA1B
IMIPRAMINE	4	CACNA1B
AMOXAPINE	4	CACNA1B
MAPROTILINE	4	CACNA1B
CLOMIPRAMINE	4	CACNA1B
NORTRIPTYLINE	4	CACNA1B
MIBEFRADIL	4	CACNA1B
ZICONOTIDE	4	CACNA1B
AMITRIPTYLINE	4	CACNA1B
PROMETHAZINE	4	CACNA1B
TRIMIPRAMINE	4	CACNA1B
PROTRIPTYLINE	4	CACNA1B
CYCLOBENZAPRINE	4	CACNA1B
DESIPRAMINE	4	CACNA1B
HESPERIDIN	3	CACNA1B
OPIPRAMOL	3	CACNA1B
CILNIDIPINE	3	CACNA1B
Z160	2	CACNA1B
SELICICLIB	2	CACNA1B
LOMERIZINE	2	CACNA1B
FLUNARIZINE	2	CACNA1B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1B
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	4	PSMF1, EMC1, KMT2B, ADD3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PSMF1	0	—
EMC1	1	—
KMT2B	15	—
ADD3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.