Neurodevelopmental disorder with microcephaly, hypotonia, and absent language

Summary

Neurodevelopmental disorder with microcephaly, hypotonia, and absent language (MONDO:0859287) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with microcephaly, hypotonia, and absent language
Mondo ID	MONDO:0859287
OMIM	620038
UMLS	C5774216
MedGen	1823989
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › neurodevelopmental disorder with microcephaly, hypotonia, and absent language

Related subtypes (20): intellectual disability, microcephaly, Williams syndrome, Aicardi syndrome, Hao-Fountain syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, complex neurodevelopmental disorder, Mendelian neurodevelopmental disorder, TCF7L2-related neurodevelopmental disorder, neurodevelopmental disorder with seizures and brain abnormalities, Yoon-Bellen neurodevelopmental syndrome, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, neurodevelopmental disorder with parkinsonism or other movement abnormalities, neurodevelopmental disorder with seizures and impaired intellectual and language development, Ebstein-Bezieau neurodevelopmental syndrome, Luo-Agrawal neurodevelopmental 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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1705855	NM_002793.4(PSMB1):c.307T>C (p.Tyr103His)	PSMB1	Pathogenic	no assertion criteria provided
4277893	NM_002793.4(PSMB1):c.49A>G (p.Met17Val)	LOC129997715	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 0 · 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
PSMB1	Moderate	Autosomal recessive	neurodevelopmental disorder	3

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
PSMB1	HGNC:9537	ENSG00000008018	P20618	Proteasome subunit beta type-1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMB1	Proteasome subunit beta type-1	Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMB1	Other/Unknown	no		Proteasome_sua/b, Proteasome_bsu_CS, Proteasome_suB-type

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
gingival epithelium	1
parietal pleura	1
pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMB1	295	ubiquitous	marker	gingival epithelium, parietal pleura, pleura

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMB1	4,652

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMB1	P20618	172

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. 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
Antigen processing: Ub, ATP-independent proteasomal degradation	1	571.0×	0.009	PSMB1
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	278.5×	0.009	PSMB1
Regulation of ornithine decarboxylase (ODC)	1	271.9×	0.009	PSMB1
Vpu mediated degradation of CD4	1	265.6×	0.009	PSMB1
Autodegradation of the E3 ubiquitin ligase COP1	1	265.6×	0.009	PSMB1
Ubiquitin-dependent degradation of Cyclin D	1	265.6×	0.009	PSMB1
Cross-presentation of soluble exogenous antigens (endosomes)	1	253.8×	0.009	PSMB1
Vif-mediated degradation of APOBEC3G	1	253.8×	0.009	PSMB1
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	248.3×	0.009	PSMB1
Degradation of AXIN	1	248.3×	0.009	PSMB1
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	248.3×	0.009	PSMB1
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	248.3×	0.009	PSMB1
Hh mutants are degraded by ERAD	1	243.0×	0.009	PSMB1
SCF-beta-TrCP mediated degradation of Emi1	1	237.9×	0.009	PSMB1
Degradation of DVL	1	237.9×	0.009	PSMB1
Negative regulation of NOTCH4 signaling	1	237.9×	0.009	PSMB1
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	237.9×	0.009	PSMB1
Regulation of RUNX3 expression and activity	1	233.1×	0.009	PSMB1
Somitogenesis	1	233.1×	0.009	PSMB1
NIK–>noncanonical NF-kB signaling	1	228.4×	0.009	PSMB1
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.009	PSMB1
Degradation of GLI1 by the proteasome	1	223.9×	0.009	PSMB1
Degradation of GLI2 by the proteasome	1	223.9×	0.009	PSMB1
GLI3 is processed to GLI3R by the proteasome	1	223.9×	0.009	PSMB1
Defective CFTR causes cystic fibrosis	1	219.6×	0.009	PSMB1
Degradation of CRY and PER proteins	1	219.6×	0.009	PSMB1
Dectin-1 mediated noncanonical NF-kB signaling	1	215.5×	0.009	PSMB1
Hedgehog ligand biogenesis	1	211.5×	0.009	PSMB1
SCF(Skp2)-mediated degradation of p27/p21	1	207.6×	0.009	PSMB1
Asymmetric localization of PCP proteins	1	203.9×	0.009	PSMB1

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
obsolete proteolysis involved in protein catabolic process	1	526.6×	0.004	PSMB1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	PSMB1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
PSMB1	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMB1	8	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMB1
CARFILZOMIB	4	PSMB1
VINBLASTINE	4	PSMB1
IXAZOMIB	3	PSMB1
MARIZOMIB	3	PSMB1
OPROZOMIB	2	PSMB1
DELANZOMIB	2	PSMB1
ZETOMIPZOMIB	2	PSMB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSMB1	309	Binding:291, ADMET:15, Functional:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSMB1	309

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

8 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)
BORTEZOMIB	4	PSMB1
CARFILZOMIB	4	PSMB1
VINBLASTINE	4	PSMB1
IXAZOMIB	3	PSMB1
MARIZOMIB	3	PSMB1
OPROZOMIB	2	PSMB1
DELANZOMIB	2	PSMB1
ZETOMIPZOMIB	2	PSMB1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMB1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.