Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

Summary

Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma (MONDO:0009633) is a disease caused by LTBP2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: LTBP2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 47

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma
Mondo ID	MONDO:0009633
OMIM	251750
UMLS	C3538951
MedGen	761238
Is cancer (heuristic)	no

Also known as: microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma · MSPKA

Data availability: 47 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › LTBP2-related ocular dysgenesis › microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma

Related subtypes (2): glaucoma 3, primary congenital, D, Weill-Marchesani syndrome 3

Subtypes (1): glaucoma secondary to spherophakia/ectopia lentis and megalocornea

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

47 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 13 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 benign, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2110814	NM_000428.3(LTBP2):c.3638dup (p.Thr1214fs)	LTBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572525	NM_000428.3(LTBP2):c.4033+1G>C	LTBP2	Pathogenic	criteria provided, single submitter
7554	NM_000428.3(LTBP2):c.895C>T (p.Arg299Ter)	LTBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1507148	NM_000428.3(LTBP2):c.2389-2A>G	LTBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
31630	NM_000428.3(LTBP2):c.4313G>A (p.Cys1438Tyr)	LTBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3237532	NM_000428.3(LTBP2):c.3652+1G>A	LTBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
126949	NM_000428.3(LTBP2):c.1295C>T (p.Pro432Leu)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126955	NM_000428.3(LTBP2):c.4250A>G (p.Gln1417Arg)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354646	NM_000428.3(LTBP2):c.654C>T (p.Cys218=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1380286	NM_000428.3(LTBP2):c.4620C>T (p.Gly1540=)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314272	NM_000428.3(LTBP2):c.4516G>A (p.Val1506Met)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314295	NM_000428.3(LTBP2):c.2788+14G>A	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
314311	NM_000428.3(LTBP2):c.1301C>T (p.Pro434Leu)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
487460	NM_000428.3(LTBP2):c.804_821dup (p.265_270PQSPPA[3])	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
595867	NM_000428.3(LTBP2):c.1686+3G>A	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
725005	NM_000428.3(LTBP2):c.1399+10G>T	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
737480	NM_000428.3(LTBP2):c.4072G>T (p.Ala1358Ser)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
785818	NM_000428.3(LTBP2):c.3611C>T (p.Ala1204Val)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
886736	NM_000428.3(LTBP2):c.2388+8C>T	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126958	NM_000428.3(LTBP2):c.4912G>A (p.Val1638Met)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1307743	NM_000428.3(LTBP2):c.1487G>A (p.Gly496Asp)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
132837	NM_000428.3(LTBP2):c.4699A>G (p.Met1567Val)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1357924	NM_000428.3(LTBP2):c.4877C>T (p.Pro1626Leu)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1362045	NM_000428.3(LTBP2):c.2012A>T (p.Gln671Leu)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1427437	NM_000428.3(LTBP2):c.2758G>A (p.Ala920Thr)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1436694	NM_000428.3(LTBP2):c.2860T>A (p.Cys954Ser)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1447800	NM_000428.3(LTBP2):c.4942G>A (p.Gly1648Arg)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1463914	NM_000428.3(LTBP2):c.4934G>A (p.Arg1645Gln)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1467459	NM_000428.3(LTBP2):c.5417C>T (p.Pro1806Leu)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1481517	NM_000428.3(LTBP2):c.4513A>G (p.Thr1505Ala)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 40 · 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
LTBP2	Definitive	Autosomal recessive	microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	20
LTBP3	Definitive	Autosomal recessive	microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
LTBP3	Orphanet:2623	Geleophysic dysplasia
LTBP3	Orphanet:2899	Brachyolmia-amelogenesis imperfecta syndrome
LTBP3	Orphanet:969	Acromicric dysplasia

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
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gencc,clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

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)
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBP2	2,658
LTBP3	2,339

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Elastic fibre formation	2	335.9×	2e-05	LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	326.3×	2e-05	LTBP2, LTBP3
Molecules associated with elastic fibres	2	308.6×	2e-05	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	200.3×	4e-05	LTBP2, LTBP3
Signaling by TGFB family members	2	115.3×	1e-04	LTBP2, LTBP3
Extracellular matrix organization	2	63.1×	3e-04	LTBP2, LTBP3
Signal Transduction	2	10.2×	0.010	LTBP2, LTBP3

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
transforming growth factor beta receptor signaling pathway	2	159.0×	5e-04	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	1203.7×	0.003	LTBP3
lung saccule development	1	1053.2×	0.003	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	1053.2×	0.003	LTBP3
supramolecular fiber organization	1	526.6×	0.004	LTBP2
positive regulation of bone resorption	1	495.6×	0.004	LTBP3
negative regulation of bone mineralization	1	468.1×	0.004	LTBP3
bone remodeling	1	468.1×	0.004	LTBP3
negative regulation of chondrocyte differentiation	1	337.0×	0.005	LTBP3
bone morphogenesis	1	300.9×	0.005	LTBP3
protein targeting	1	183.2×	0.007	LTBP2
chondrocyte differentiation	1	150.5×	0.008	LTBP3
bone mineralization	1	135.9×	0.008	LTBP3
protein secretion	1	131.7×	0.008	LTBP2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LTBP2	0	0
LTBP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	2	LTBP2, LTBP3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.