Nephrotic syndrome, type 4

Summary

Nephrotic syndrome, type 4 (MONDO:0009733) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 256

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrotic syndrome, type 4
Mondo ID	MONDO:0009733
OMIM	256370
DOID	DOID:0080383
NCIT	C121198
UMLS	C3151568
MedGen	462918
GARD	0015210
Is cancer (heuristic)	no

Also known as: congenital nephrotic syndrome - diffuse mesangial sclerosis · diffuse isolated mesangial sclerosis · diffuse mesangial sclerosis · DMS · familial mesangial sclerosis · isolated diffuse mesangial sclerosis · mesangial sclerosis, diffuse · nephrotic syndrome caused by mutation in WT1 · nephrotic syndrome, early onset with diffuse mesangial sclerosis · nephrotic syndrome, type 4 · NPHS4 · WT1 nephrotic syndrome

Data availability: 256 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome › nephrotic syndrome, type 4

Related subtypes (17): congenital nephrotic syndrome, Finnish type, LAMB2-related infantile-onset nephrotic syndrome, immunoglobulin-mediated membranoproliferative glomerulonephritis, familial idiopathic steroid-resistant nephrotic syndrome, nephrotic syndrome, type 20, nephrotic syndrome, type 22, nephrotic syndrome, type 23, nephrotic syndrome, type 24, nephrotic syndrome, IIa 26, nephrotic syndrome, type 17, nephrotic syndrome, type 18, nephrotic syndrome, type 19, nephrotic syndrome, type 21, nephrotic syndrome 14, nephrotic syndrome 15, nephrotic syndrome 16, idiopathic multidrug-resistant nephrotic 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

256 retrieved; paginated sample, class counts are floors:

115 uncertain significance, 64 conflicting classifications of pathogenicity, 20 benign/likely benign, 14 benign, 13 likely pathogenic, 12 pathogenic, 11 likely benign, 7 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
978564	NM_024426.6(WT1):c.278G>C (p.Gly93Ala)	LOC107982234	Pathogenic	criteria provided, single submitter
1077036	NM_024426.6(WT1):c.1534C>T (p.Gln512Ter)	WT1	Pathogenic	criteria provided, single submitter
2584482	NM_024426.6(WT1):c.1354+2T>C	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3487	NM_024426.6(WT1):c.1399C>T (p.Arg467Trp)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3488	NM_024426.6(WT1):c.1316G>A (p.Arg439His)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3490	NM_024426.6(WT1):c.1405G>A (p.Asp469Asn)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3493	NM_024426.6(WT1):c.1447+5G>A	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3494	NM_024426.6(WT1):c.1387C>T (p.Arg463Ter)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3495	NM_024426.6(WT1):c.1348C>T (p.His450Tyr)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3497	NM_024426.6(WT1):c.1303C>T (p.Arg435Ter)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3500	NM_024426.6(WT1):c.1447+4C>T	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3502	NM_024426.6(WT1):c.1366T>C (p.Phe456Leu)	WT1	Pathogenic	no assertion criteria provided
3505	NM_024426.6(WT1):c.1315C>T (p.Arg439Cys)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
3599545	NM_024426.6(WT1):c.1397C>T (p.Ser466Phe)	WT1	Pathogenic	criteria provided, single submitter
3769629	NM_024426.6(WT1):c.1324C>T (p.Gln442Ter)	WT1	Pathogenic	criteria provided, single submitter
419332	NM_024426.6(WT1):c.1400G>A (p.Arg467Gln)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438653	NM_024426.6(WT1):c.512G>T (p.Gly171Val)	WT1	Pathogenic	criteria provided, single submitter
547167	NM_024426.6(WT1):c.1405G>T (p.Asp469Tyr)	WT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
664113	NM_024426.6(WT1):c.1499G>A (p.Arg500Gln)	WT1	Pathogenic	criteria provided, multiple submitters, no conflicts
4293614	NM_024426.6(WT1):c.363C>G (p.Tyr121Ter)	LOC107982234	Likely pathogenic	criteria provided, single submitter
872897	NM_024426.6(WT1):c.500T>A (p.Val167Asp)	LOC107982234	Likely pathogenic	criteria provided, single submitter
1708395	NM_024426.6(WT1):c.1322A>T (p.Asp441Val)	WT1	Likely pathogenic	criteria provided, single submitter
2505271	NM_024426.6(WT1):c.1498C>T (p.Arg500Trp)	WT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2584358	NM_024426.6(WT1):c.1268A>G (p.Glu423Gly)	WT1	Likely pathogenic	criteria provided, single submitter
2681776	NM_024426.6(WT1):c.1384C>T (p.Gln462Ter)	WT1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2681777	NM_024426.6(WT1):c.896T>A (p.Leu299Ter)	WT1	Likely pathogenic	criteria provided, single submitter
2681778	NM_024426.6(WT1):c.1394T>C (p.Phe465Ser)	WT1	Likely pathogenic	criteria provided, single submitter
2681779	NM_024426.6(WT1):c.1367T>G (p.Phe456Cys)	WT1	Likely pathogenic	criteria provided, single submitter
2681780	NM_024426.6(WT1):c.1504G>C (p.Asp502His)	WT1	Likely pathogenic	criteria provided, single submitter
3599543	NM_024426.6(WT1):c.1498del (p.Arg500fs)	WT1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WT1	Orphanet:220	Denys-Drash syndrome
WT1	Orphanet:242	46,XY complete gonadal dysgenesis
WT1	Orphanet:251510	46,XY partial gonadal dysgenesis
WT1	Orphanet:3097	Meacham syndrome
WT1	Orphanet:347	Frasier syndrome
WT1	Orphanet:654	Nephroblastoma
WT1	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
WT1	Orphanet:83469	Desmoplastic small round cell tumor
WT1	Orphanet:893	WAGR syndrome

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
WT1	HGNC:12796	ENSG00000184937	P19544	Wilms tumor protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WT1	Wilms tumor protein	Transcription factor that plays an important role in cellular development and cell survival.

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)
WT1	Transcription factor	no		Wilms_tumour_N, Znf_C2H2_type, Znf_C2H2_sf

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
germinal epithelium of ovary	1
metanephric glomerulus	1
renal glomerulus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WT1	168	broad	marker	germinal epithelium of ovary, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WT1	3,938

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WT1	P19544	28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Nephron development	1	878.5×	0.002	WT1
Transcriptional regulation of testis differentiation	1	713.8×	0.002	WT1
Negative Regulation of CDH1 Gene Transcription	1	120.2×	0.008	WT1

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
negative regulation of metanephric glomerular mesangial cell proliferation	1	16852.0×	1e-03	WT1
regulation of animal organ formation	1	8426.0×	1e-03	WT1
adrenal cortex formation	1	8426.0×	1e-03	WT1
visceral serous pericardium development	1	8426.0×	1e-03	WT1
posterior mesonephric tubule development	1	8426.0×	1e-03	WT1
positive regulation of metanephric ureteric bud development	1	8426.0×	1e-03	WT1
positive regulation of heart growth	1	4213.0×	0.001	WT1
metanephric S-shaped body morphogenesis	1	4213.0×	0.001	WT1
negative regulation of female gonad development	1	4213.0×	0.001	WT1
thorax and anterior abdomen determination	1	3370.4×	0.001	WT1
cardiac muscle cell fate commitment	1	3370.4×	0.001	WT1
metanephric epithelium development	1	3370.4×	0.001	WT1
cellular response to gonadotropin stimulus	1	2808.7×	0.001	WT1
metanephric mesenchyme development	1	2407.4×	0.001	WT1
tissue development	1	1872.4×	0.002	WT1
diaphragm development	1	1872.4×	0.002	WT1
sex determination	1	1685.2×	0.002	WT1
positive regulation of male gonad development	1	1685.2×	0.002	WT1
glomerular basement membrane development	1	1532.0×	0.002	WT1
mesenchymal to epithelial transition	1	1532.0×	0.002	WT1
podocyte differentiation	1	1404.3×	0.002	WT1
glomerulus development	1	1296.3×	0.002	WT1
gonad development	1	1123.5×	0.002	WT1
negative regulation of gene expression via chromosomal CpG island methylation	1	1053.2×	0.002	WT1
male genitalia development	1	887.0×	0.002	WT1
adrenal gland development	1	674.1×	0.003	WT1
ureteric bud development	1	455.5×	0.004	WT1
germ cell development	1	455.5×	0.004	WT1
branching involved in ureteric bud morphogenesis	1	366.4×	0.005	WT1
camera-type eye development	1	358.6×	0.005	WT1

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
WT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	WT1

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)
WT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.