Geleophysic dysplasia 1

Summary

Geleophysic dysplasia 1 (MONDO:0009269) is a disease caused by ADAMTSL2 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ADAMTSL2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 162

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	geleophysic dysplasia 1
Mondo ID	MONDO:0009269
OMIM	231050
DOID	DOID:0111725
UMLS	C3278147
MedGen	479777
GARD	0015172
Is cancer (heuristic)	no

Also known as: ADAMTSL2 geleophysic dysplasia · geleophysic dysplasia 1 · geleophysic dysplasia caused by mutation in ADAMTSL2 · Geleophysic dysplasia type 1 · GPHYSD1

Data availability: 162 ClinVar variants · 4 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › acromelic dysplasia › geleophysic dysplasia › geleophysic dysplasia 1

Related subtypes (2): geleophysic dysplasia 2, geleophysic dysplasia 3

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

162 retrieved; paginated sample, class counts are floors:

104 uncertain significance, 22 conflicting classifications of pathogenicity, 15 benign, 7 likely pathogenic, 7 pathogenic, 3 likely benign, 3 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30945	NM_014694.4(ADAMTSL2):c.661C>T (p.Arg221Cys)	ADAMTSL2	Pathogenic	no assertion criteria provided
427943	NM_014694.4(ADAMTSL2):c.234-2A>G	ADAMTSL2	Pathogenic	no assertion criteria provided
624558	NM_014694.4(ADAMTSL2):c.499G>A (p.Asp167Asn)	ADAMTSL2	Pathogenic	no assertion criteria provided
693	NM_014694.4(ADAMTSL2):c.440C>T (p.Pro147Leu)	ADAMTSL2	Pathogenic	no assertion criteria provided
696	NM_014694.4(ADAMTSL2):c.2431G>A (p.Gly811Arg)	ADAMTSL2	Pathogenic	no assertion criteria provided
697	NM_014694.4(ADAMTSL2):c.2586G>A (p.Trp862Ter)	ADAMTSL2	Pathogenic	no assertion criteria provided
915302	NM_014694.4(ADAMTSL2):c.529C>T (p.Arg177Ter)	ADAMTSL2	Pathogenic	criteria provided, single submitter
1324686	NM_001130144.3(LTBP3):c.3574G>T (p.Glu1192Ter)	LTBP3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1162207	NM_014694.4(ADAMTSL2):c.2737+1G>T	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
1164089	NM_014694.4(ADAMTSL2):c.337C>T (p.Arg113Cys)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326072	NM_014694.4(ADAMTSL2):c.338G>T (p.Arg113Leu)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1710157	NM_014694.4(ADAMTSL2):c.1061del (p.Gly354fs)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
30944	NM_014694.4(ADAMTSL2):c.215G>A (p.Arg72Gln)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
3596752	NM_014694.4(ADAMTSL2):c.799G>A (p.Gly267Ser)	ADAMTSL2	Likely pathogenic	criteria provided, single submitter
694	NM_014694.4(ADAMTSL2):c.338G>A (p.Arg113His)	ADAMTSL2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
365571	NM_014694.4(ADAMTSL2):c.58G>A (p.Val20Ile)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365594	NM_014694.4(ADAMTSL2):c.1280G>A (p.Arg427His)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365599	NM_014694.4(ADAMTSL2):c.1641C>T (p.His547=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365601	NM_014694.4(ADAMTSL2):c.2049C>T (p.Pro683=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365603	NM_014694.4(ADAMTSL2):c.2142G>A (p.Ser714=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365604	NM_014694.4(ADAMTSL2):c.2325C>G (p.Ser775=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365605	NM_014694.4(ADAMTSL2):c.2436C>T (p.Arg812=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365609	NM_014694.4(ADAMTSL2):c.2520C>T (p.Ala840=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
365611	NM_014694.4(ADAMTSL2):c.2613G>A (p.Val871=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518395	NM_014694.4(ADAMTSL2):c.2022C>T (p.Pro674=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
518396	NM_014694.4(ADAMTSL2):c.2313A>G (p.Val771=)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695	NM_014694.4(ADAMTSL2):c.340G>A (p.Glu114Lys)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912944	NM_014694.4(ADAMTSL2):c.2036C>G (p.Thr679Ser)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
912995	NM_014694.4(ADAMTSL2):c.*287C>A	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
913274	NM_014694.4(ADAMTSL2):c.1261G>A (p.Gly421Ser)	ADAMTSL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 8 · 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
ADAMTSL2	Definitive	Autosomal recessive	geleophysic dysplasia 1	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTSL2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:2623	Geleophysic dysplasia
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTSL2	HGNC:14631	ENSG00000197859	Q86TH1	ADAMTS-like protein 2	gencc,clinvar
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	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: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTSL2	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC
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.

3 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
ascending aorta	2
descending thoracic aorta	2
thoracic aorta	2
cardiac atrium	1
metanephros cortex	1
right atrium auricular region	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTSL2	159	broad	marker	right atrium auricular region, metanephros cortex, cardiac atrium
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: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBP2	2,658
LTBP3	2,339
ADAMTSL2	600

Intra-cohort edges

A	B	Sources
ADAMTSL2	LTBP3	string_interaction

Structural data

PDB: 0 · AlphaFold-only: 3 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTSL2	Q86TH1	67.10
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Elastic fibre formation	2	223.9×	2e-04	LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	217.5×	2e-04	LTBP2, LTBP3
Molecules associated with elastic fibres	2	205.8×	2e-04	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	133.6×	3e-04	LTBP2, LTBP3
Signaling by TGFB family members	2	76.9×	7e-04	LTBP2, LTBP3
Extracellular matrix organization	2	42.1×	0.002	LTBP2, LTBP3
Defective B3GALTL causes PpS	1	102.9×	0.020	ADAMTSL2
O-glycosylation of TSR domain-containing proteins	1	100.2×	0.020	ADAMTSL2
Diseases associated with O-glycosylation of proteins	1	71.8×	0.025	ADAMTSL2
O-linked glycosylation	1	48.2×	0.033	ADAMTSL2
Diseases of glycosylation	1	43.8×	0.033	ADAMTSL2
Signal Transduction	2	6.8×	0.036	LTBP2, LTBP3
Diseases of metabolism	1	26.8×	0.045	ADAMTSL2
Post-translational protein modification	1	6.4×	0.170	ADAMTSL2
Disease	1	4.4×	0.223	ADAMTSL2
Metabolism of proteins	1	4.1×	0.223	ADAMTSL2

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
lobar bronchus epithelium development	1	5617.3×	0.002	ADAMTSL2
transforming growth factor beta receptor signaling pathway	2	106.0×	0.002	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	802.5×	0.005	LTBP3
lung saccule development	1	702.2×	0.005	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	702.2×	0.005	LTBP3
supramolecular fiber organization	1	351.1×	0.006	LTBP2
positive regulation of bone resorption	1	330.4×	0.006	LTBP3
negative regulation of bone mineralization	1	312.1×	0.006	LTBP3
bone remodeling	1	312.1×	0.006	LTBP3
negative regulation of chondrocyte differentiation	1	224.7×	0.008	LTBP3
bone morphogenesis	1	200.6×	0.008	LTBP3
protein targeting	1	122.1×	0.012	LTBP2
chondrocyte differentiation	1	100.3×	0.013	LTBP3
bone mineralization	1	90.6×	0.013	LTBP3
protein secretion	1	87.8×	0.013	LTBP2
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.018	ADAMTSL2
extracellular matrix organization	1	40.7×	0.024	ADAMTSL2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
ADAMTSL2	0	0
LTBP2	0	0
LTBP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	ADAMTSL2, LTBP2, LTBP3

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)
ADAMTSL2	0	—
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.