Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

Summary

Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism (MONDO:0958231) is a disease caused by PUM1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PUM1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 9

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism
Mondo ID	MONDO:0958231
OMIM	620719
Orphanet	589515
GARD	0027314
Is cancer (heuristic)	no

Also known as: PUM1-associated developmental disability-ataxia-seizure syndrome

Data availability: 9 ClinVar variants · 2 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 › epilepsy › monogenic epilepsy › neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, severe neonatal-onset encephalopathy with microcephaly, familial infantile myoclonic epilepsy, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, polyhydramnios, megalencephaly, and symptomatic epilepsy, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features

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

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 conflicting classifications of pathogenicity, 2 likely pathogenic, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3777062	NM_001020658.2(PUM1):c.1159del (p.Leu387fs)	PUM1	Pathogenic	criteria provided, single submitter
617918	NM_001020658.2(PUM1):c.3439C>T (p.Arg1147Trp)	PUM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3600359	NM_001020658.2(PUM1):c.2264_2291dup (p.Ser765fs)	PUM1	Likely pathogenic	criteria provided, single submitter
617929	NM_001020658.2(PUM1):c.3415C>T (p.Arg1139Trp)	PUM1	Likely pathogenic	criteria provided, single submitter
2232761	NM_001020658.2(PUM1):c.1237C>T (p.His413Tyr)	PUM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3892233	NM_001020658.2(PUM1):c.218G>T (p.Gly73Val)	PUM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3064713	NM_001020658.2(PUM1):c.2342G>A (p.Ser781Asn)	PUM1	Uncertain significance	criteria provided, single submitter
3892234	NM_001020658.2(PUM1):c.775_777dup (p.Gly259_Thr260insGly)	PUM1	Uncertain significance	criteria provided, single submitter
977328	NM_001020658.2(PUM1):c.1927A>G (p.Ser643Gly)	PUM1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PUM1	Strong	Autosomal dominant	neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PUM1	Orphanet:589515	PUM1-associated developmental disability-ataxia-seizure syndrome
PUM1	Orphanet:642747	PUM1-related cerebellar ataxia

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
PUM1	HGNC:14957	ENSG00000134644	Q14671	Pumilio homolog 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PUM1	Pumilio homolog 1	Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3’-UTR of mRNA targets.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PUM1	Transcription factor	no		Pumilio_RNA-bd_rpt, ARM-like, ARM-type_fold

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
CA1 field of hippocampus	1
dorsal motor nucleus of vagus nerve	1
germinal epithelium of ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PUM1	303	ubiquitous	marker	dorsal motor nucleus of vagus nerve, CA1 field of hippocampus, germinal epithelium of ovary

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PUM1	5,826

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PUM1	Q14671	15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Golgi Associated Vesicle Biogenesis	1	200.3×	0.005	PUM1

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
regulation of miRNA-mediated gene silencing	1	5617.3×	0.002	PUM1
post-transcriptional gene silencing	1	4213.0×	0.002	PUM1
positive regulation of miRNA-mediated gene silencing	1	2407.4×	0.002	PUM1
regulation of chromosome segregation	1	1872.4×	0.002	PUM1
positive regulation of RIG-I signaling pathway	1	1532.0×	0.002	PUM1
miRNA processing	1	1053.2×	0.002	PUM1
3’-UTR-mediated mRNA destabilization	1	766.0×	0.003	PUM1
mRNA destabilization	1	674.1×	0.003	PUM1
post-transcriptional regulation of gene expression	1	648.1×	0.003	PUM1
regulation of mRNA stability	1	421.3×	0.004	PUM1
adult locomotory behavior	1	300.9×	0.004	PUM1
stem cell differentiation	1	300.9×	0.004	PUM1
regulation of translation	1	218.9×	0.005	PUM1
regulation of cell cycle	1	74.6×	0.014	PUM1
spermatogenesis	1	35.2×	0.028	PUM1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PUM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PUM1	1	Binding:1

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	1	PUM1

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)
PUM1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.