Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss

Summary

Neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss (MONDO:0859296) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss
Mondo ID	MONDO:0859296
OMIM	620071
DOID	DOID:0081324
UMLS	C5774229
MedGen	1824002
Is cancer (heuristic)	no

Data availability: 1 ClinVar variant · 3 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 poor growth, spastic tetraplegia, and hearing loss

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 microcephaly, hypotonia, and absent language, 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

1 retrieved; paginated sample, class counts are floors:

1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1710322	NM_002802.3(PSMC1):c.983T>C (p.Ile328Thr)	NRDE2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
PSMC1	Limited	Autosomal recessive	neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss	4

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSMC1	HGNC:9547	ENSG00000100764	P62191	26S proteasome regulatory subunit 4	gencc
NRDE2	HGNC:20186	ENSG00000119720	Q9H7Z3	Nuclear exosome regulator NRDE2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMC1	26S proteasome regulatory subunit 4	Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins.
NRDE2	Nuclear exosome regulator NRDE2	Protein of the nuclear speckles that regulates RNA degradation and export from the nucleus through its interaction with MTREX an essential factor directing various RNAs to exosomal degradation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMC1	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
NRDE2	Other/Unknown	no		TPR-like_helical_dom_sf, NRDE-2

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
gastrocnemius	1
muscle of leg	1
bone marrow cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMC1	144	ubiquitous	marker	calcaneal tendon, gastrocnemius, muscle of leg
NRDE2	225	ubiquitous	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NRDE2	1,425
PSMC1	1,117

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMC1	P62191	131
NRDE2	Q9H7Z3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 2 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
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	423.0×	0.008	PSMC1
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	278.5×	0.008	PSMC1
Regulation of ornithine decarboxylase (ODC)	1	271.9×	0.008	PSMC1
Vpu mediated degradation of CD4	1	265.6×	0.008	PSMC1
Autodegradation of the E3 ubiquitin ligase COP1	1	265.6×	0.008	PSMC1
Ubiquitin-dependent degradation of Cyclin D	1	265.6×	0.008	PSMC1
Cross-presentation of soluble exogenous antigens (endosomes)	1	253.8×	0.008	PSMC1
Vif-mediated degradation of APOBEC3G	1	253.8×	0.008	PSMC1
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	248.3×	0.008	PSMC1
Degradation of AXIN	1	248.3×	0.008	PSMC1
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	248.3×	0.008	PSMC1
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	248.3×	0.008	PSMC1
Hh mutants are degraded by ERAD	1	243.0×	0.008	PSMC1
SCF-beta-TrCP mediated degradation of Emi1	1	237.9×	0.008	PSMC1
Degradation of DVL	1	237.9×	0.008	PSMC1
Negative regulation of NOTCH4 signaling	1	237.9×	0.008	PSMC1
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	237.9×	0.008	PSMC1
Regulation of RUNX3 expression and activity	1	233.1×	0.008	PSMC1
Somitogenesis	1	233.1×	0.008	PSMC1
NIK–>noncanonical NF-kB signaling	1	228.4×	0.008	PSMC1
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	228.4×	0.008	PSMC1
Degradation of GLI1 by the proteasome	1	223.9×	0.008	PSMC1
Degradation of GLI2 by the proteasome	1	223.9×	0.008	PSMC1
GLI3 is processed to GLI3R by the proteasome	1	223.9×	0.008	PSMC1
Defective CFTR causes cystic fibrosis	1	219.6×	0.008	PSMC1
Degradation of CRY and PER proteins	1	219.6×	0.008	PSMC1
Dectin-1 mediated noncanonical NF-kB signaling	1	215.5×	0.008	PSMC1
Hedgehog ligand biogenesis	1	211.5×	0.008	PSMC1
SCF(Skp2)-mediated degradation of p27/p21	1	207.6×	0.008	PSMC1
Asymmetric localization of PCP proteins	1	203.9×	0.008	PSMC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of RNA catabolic process	1	8426.0×	0.001	NRDE2
positive regulation of RNA export from nucleus	1	1685.2×	0.003	NRDE2
regulatory ncRNA-mediated heterochromatin formation	1	936.2×	0.004	NRDE2
mRNA stabilization	1	183.2×	0.014	NRDE2
mitotic cell cycle	1	66.9×	0.030	NRDE2
RNA splicing	1	44.1×	0.036	NRDE2
mRNA processing	1	39.4×	0.036	NRDE2
DNA damage response	1	26.8×	0.042	NRDE2
proteasome-mediated ubiquitin-dependent protein catabolic process	1	26.1×	0.042	PSMC1
cell division	1	23.1×	0.043	NRDE2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
PSMC1	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMC1	2	4
NRDE2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMC1
CARFILZOMIB	4	PSMC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSMC1	27	Binding:27

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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	PSMC1
CARFILZOMIB	4	PSMC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMC1
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	NRDE2

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)
NRDE2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.