LAMB2-related infantile-onset nephrotic syndrome

Summary

LAMB2-related infantile-onset nephrotic syndrome (MONDO:0013621) is a disease caused by LAMB2 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: LAMB2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 1,138

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	LAMB2-related infantile-onset nephrotic syndrome
Mondo ID	MONDO:0013621
MeSH	C565405
OMIM	249660, 614199
Orphanet	306507
DOID	DOID:0080380
UMLS	C3280113
MedGen	481743
GARD	0027849
Is cancer (heuristic)	no

Also known as: mesangial sclerosis, diffuse renal, with ocular abnormalities · nephrotic syndrome, type 5, with or without ocular abnormalities · NPHS5

Data availability: 1,138 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › syndromic disease › nephrotic syndrome › familial nephrotic syndrome › LAMB2-related infantile-onset nephrotic syndrome

Related subtypes (17): congenital nephrotic syndrome, Finnish type, nephrotic syndrome, type 4, 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

Subtypes (1): Pierson 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

600 retrieved; paginated sample, class counts are floors:

281 uncertain significance, 223 likely benign, 32 conflicting classifications of pathogenicity, 30 pathogenic, 11 benign/likely benign, 9 pathogenic/likely pathogenic, 8 benign, 6 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
14535	NM_002292.3(LAMB2):c.[4140C>A;4177C>T]		Pathogenic	no assertion criteria provided
1032809	NM_002292.4(LAMB2):c.2344+1G>A	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179056	NM_002292.4(LAMB2):c.1564del (p.Cys522fs)	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179149	NM_002292.4(LAMB2):c.1276del (p.His426fs)	LAMB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323180	NM_002292.3(LAMB2):c.1037_1038del	LAMB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323182	NM_002292.4(LAMB2):c.3595C>T (p.Arg1199Ter)	LAMB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1323183	NM_002292.4(LAMB2):c.3207dup (p.Asn1070fs)	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333511	NM_002292.4(LAMB2):c.4904_4905del (p.Thr1635fs)	LAMB2	Pathogenic	criteria provided, single submitter
1344739	NM_002292.4(LAMB2):c.4573C>T (p.Gln1525Ter)	LAMB2	Pathogenic	criteria provided, multiple submitters, no conflicts
1366297	NM_002292.4(LAMB2):c.4201del (p.Ser1401fs)	LAMB2	Pathogenic	criteria provided, single submitter
1377324	NM_002292.4(LAMB2):c.3882_3892del (p.Asn1294fs)	LAMB2	Pathogenic	criteria provided, single submitter
1446226	NM_002292.4(LAMB2):c.3477_3483del (p.Gly1160fs)	LAMB2	Pathogenic	criteria provided, single submitter
14530	NM_002292.4(LAMB2):c.736C>T (p.Arg246Trp)	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14532	NM_002292.4(LAMB2):c.2067C>G (p.Tyr689Ter)	LAMB2	Pathogenic	criteria provided, single submitter
1453552	NM_002292.4(LAMB2):c.1390_1391insA (p.Arg464fs)	LAMB2	Pathogenic	criteria provided, single submitter
14536	NM_002292.4(LAMB2):c.961T>C (p.Cys321Arg)	LAMB2	Pathogenic	no assertion criteria provided
14537	NM_002292.4(LAMB2):c.1478del (p.Cys493fs)	LAMB2	Pathogenic	no assertion criteria provided
14538	NM_002292.4(LAMB2):c.4804del (p.Gln1602fs)	LAMB2	Pathogenic	criteria provided, single submitter
1455722	NM_002292.4(LAMB2):c.1934dup (p.Gly646fs)	LAMB2	Pathogenic	criteria provided, single submitter
1456187	NM_002292.4(LAMB2):c.1241_1242dup (p.Met415fs)	LAMB2	Pathogenic	criteria provided, single submitter
1686687	NM_002292.4(LAMB2):c.4822C>T (p.Gln1608Ter)	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1712424	NM_002292.4(LAMB2):c.2369C>G (p.Ser790Ter)	LAMB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1976270	NM_002292.4(LAMB2):c.3251G>A (p.Trp1084Ter)	LAMB2	Pathogenic	criteria provided, single submitter
1998213	NM_002292.4(LAMB2):c.752_756dup (p.His253fs)	LAMB2	Pathogenic	criteria provided, single submitter
2002665	NM_002292.4(LAMB2):c.2249dup (p.His750fs)	LAMB2	Pathogenic	criteria provided, single submitter
2021063	NM_002292.4(LAMB2):c.3690_3697del (p.Ser1230fs)	LAMB2	Pathogenic	criteria provided, single submitter
2115550	NM_002292.4(LAMB2):c.3328-1G>C	LAMB2	Pathogenic	criteria provided, single submitter
2115551	NM_002292.4(LAMB2):c.2018+2T>C	LAMB2	Pathogenic	criteria provided, single submitter
2116167	NM_002292.4(LAMB2):c.4806_4807del (p.Lys1603fs)	LAMB2	Pathogenic	criteria provided, single submitter
2116168	NM_002292.4(LAMB2):c.2884+1del	LAMB2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
LAMB2	Strong	Autosomal recessive	LAMB2-related infantile-onset nephrotic syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LAMB2	Orphanet:2670	Pierson syndrome
LAMB2	Orphanet:98915	Synaptic congenital myasthenic syndrome
DAG1	Orphanet:206599	Isolated asymptomatic elevation of creatine phosphokinase
DAG1	Orphanet:280333	Alpha-dystroglycan-related limb-girdle muscular dystrophy R16
DAG1	Orphanet:370997	Muscle-eye-brain disease with bilateral multicystic leucodystrophy
DAG1	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LAMB2	HGNC:6487	ENSG00000172037	P55268	Laminin subunit beta-2	gencc,clinvar
SERPINA10	HGNC:15996	ENSG00000140093	Q9UK55	Protein Z-dependent protease inhibitor	clinvar
DAG1	HGNC:2666	ENSG00000173402	Q14118	Dystroglycan 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LAMB2	Laminin subunit beta-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
SERPINA10	Protein Z-dependent protease inhibitor	Inhibits activity of the coagulation protease factor Xa in the presence of PROZ, calcium and phospholipids.
DAG1	Dystroglycan 1	The dystroglycan complex is involved in a number of signaling events and processes including laminin deposition and extracellular matrix assembly, acetylcholine receptor clustering, sarcolemmal stability, cell survival, peripheral nerve my…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LAMB2	Other/Unknown	no		EGF, LE_dom, Laminin_N
SERPINA10	Other/Unknown	no		Serpin_fam, Serpin_dom, PZI_serpin_dom
DAG1	Antibody/Immunoglobulin	yes		Cadg, DAG1_C, Ig-like_fold

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
right lobe of thyroid gland	1
stromal cell of endometrium	1
islet of Langerhans	1
liver	1
right lobe of liver	1
dorsal root ganglion	1
olfactory bulb	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LAMB2	268	ubiquitous	marker	apex of heart, right lobe of thyroid gland, stromal cell of endometrium
SERPINA10	106	tissue_specific	yes	right lobe of liver, liver, islet of Langerhans
DAG1	299	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DAG1	2,301
LAMB2	1,548
SERPINA10	951

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DAG1	Q14118	8
SERPINA10	Q9UK55	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LAMB2	P55268	75.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the dystrophin-glycoprotein complex (DGC)	2	205.8×	8e-04	LAMB2, DAG1
Non-integrin membrane-ECM interactions	2	102.9×	0.001	LAMB2, DAG1
ECM proteoglycans	2	100.2×	0.001	LAMB2, DAG1
Post-translational protein phosphorylation	2	66.8×	0.002	LAMB2, SERPINA10
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	2	57.7×	0.002	LAMB2, SERPINA10
Defective POMGNT1 causes MDDGA3, MDDGB3 and MDDGC3	1	1903.3×	0.002	DAG1
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	1268.9×	0.003	DAG1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	1268.9×	0.003	DAG1
DAG1 core M1 glycosylations	1	951.7×	0.003	DAG1
DAG1 core M2 glycosylations	1	761.3×	0.003	DAG1
DAG1 core M3 glycosylations	1	634.4×	0.004	DAG1
Matriglycan biosynthesis on DAG1	1	271.9×	0.008	DAG1
MET promotes cell motility	1	200.3×	0.010	LAMB2
Attachment of bacteria to epithelial cells	1	165.5×	0.011	LAMB2
Laminin interactions	1	126.9×	0.012	LAMB2
MET activates PTK2 signaling	1	126.9×	0.012	LAMB2
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.012	DAG1
Signaling by MET	1	105.7×	0.014	LAMB2
Regulation of clotting cascade	1	77.7×	0.017	SERPINA10
Developmental Lineage of Pancreatic Ductal Cells	1	76.1×	0.017	LAMB2
Regulation of expression of SLITs and ROBOs	1	23.1×	0.053	DAG1
Extracellular matrix organization	1	21.0×	0.055	LAMB2
Signaling by Receptor Tyrosine Kinases	1	17.2×	0.064	LAMB2
Post-translational protein modification	1	6.4×	0.161	LAMB2
Metabolism of proteins	1	4.1×	0.232	LAMB2
Signal Transduction	1	3.4×	0.267	LAMB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle attachment	1	5617.3×	0.003	DAG1
nerve maturation	1	5617.3×	0.003	DAG1
metanephric glomerular basement membrane development	1	5617.3×	0.003	LAMB2
calcium-dependent cell-matrix adhesion	1	2808.7×	0.003	DAG1
metanephric podocyte development	1	2808.7×	0.003	LAMB2
axon guidance	2	60.4×	0.003	LAMB2, DAG1
axon extension involved in regeneration	1	1872.4×	0.003	LAMB2
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	1872.4×	0.003	DAG1
regulation of basement membrane organization	1	936.2×	0.006	LAMB2
response to denervation involved in regulation of muscle adaptation	1	802.5×	0.006	DAG1
morphogenesis of an epithelial sheet	1	561.7×	0.007	DAG1
angiogenesis involved in wound healing	1	561.7×	0.007	DAG1
radial glial cell differentiation	1	510.7×	0.007	LAMB2
branching involved in salivary gland morphogenesis	1	468.1×	0.007	DAG1
microtubule anchoring	1	432.1×	0.007	DAG1
positive regulation of integrin-mediated signaling pathway	1	432.1×	0.007	LAMB2
astrocyte development	1	374.5×	0.007	LAMB2
axon regeneration	1	374.5×	0.007	DAG1
positive regulation of muscle cell differentiation	1	374.5×	0.007	LAMB2
Schwann cell development	1	351.1×	0.007	LAMB2
commissural neuron axon guidance	1	330.4×	0.007	DAG1
nerve development	1	312.1×	0.007	DAG1
myelination in peripheral nervous system	1	295.6×	0.007	DAG1
skeletal muscle tissue regeneration	1	295.6×	0.007	DAG1
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	295.6×	0.007	DAG1
epithelial tube branching involved in lung morphogenesis	1	280.9×	0.007	DAG1
cellular response to cholesterol	1	280.9×	0.007	DAG1
positive regulation of myelination	1	255.3×	0.007	DAG1
positive regulation of cell-matrix adhesion	1	224.7×	0.007	DAG1
positive regulation of oligodendrocyte differentiation	1	224.7×	0.007	DAG1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LAMB2	0	0
SERPINA10	0	0
DAG1	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
DAG1	4	Binding:4

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	1	DAG1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LAMB2, SERPINA10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LAMB2	0	—
SERPINA10	0	—
DAG1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.