Bone fragility with contractures, arterial rupture, and deafness

Summary

Bone fragility with contractures, arterial rupture, and deafness (MONDO:0012892) is a disease caused by PLOD3 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLOD3 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	bone fragility with contractures, arterial rupture, and deafness
Mondo ID	MONDO:0012892
MeSH	C567320
OMIM	612394
Orphanet	300284
DOID	DOID:0061197
SNOMED CT	763318007
UMLS	C2676285
MedGen	382811
GARD	0017362
Is cancer (heuristic)	no

Also known as: bone fragility with contractures, arterial rupture, and deafness · bone fragility-contractures-arterial rupture-deafness syndrome · connective tissue disorder due to LH3 deficiency · connective tissue disorder due to lysyl hydroxylase-3 deficiency

Data availability: 29 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › bone fragility with contractures, arterial rupture, and deafness

Related subtypes (51): disorder of sexual differentiation, hereditary neurocutaneous angioma, nevoid basal cell carcinoma syndrome, angioosteohypertrophic syndrome, Larsen syndrome, schwannomatosis, linear nevus sebaceous syndrome, lethal Larsen-like syndrome, pseudodiastrophic dysplasia, focal dermal hypoplasia, microtia, neurofibromatosis-Noonan syndrome, Becker nevus syndrome, Legius syndrome, blindness - scoliosis - arachnodactyly syndrome, cutis laxa - Marfanoid syndrome, Maffucci syndrome, hydrops fetalis, ankyloblepharon filiforme-imperforate anus syndrome, developmental anomaly of metabolic origin, progeroid syndrome, facial cleft, Desbuquois dysplasia, cysts and fistulae of the face and oral cavity, macroglossia, middle ear anomaly, cleft palate, cutis laxa, infectious embryofetopathy, toxic or drug-related embryofetopathy, hemihyperplasia-multiple lipomatosis syndrome, phakomatosis pigmentokeratotica, phakomatosis pigmentovascularis, PTEN hamartoma tumor syndrome, marfanoid habitus-inguinal hernia-advanced bone age syndrome, neurofibromatosis type 1, multiple congenital anomalies/dysmorphic syndrome, congenital limb malformation, hereditary hemorrhagic telangiectasia, urogenital tract malformation, congenital anomaly of kidney and urinary tract, anotia, central nervous system malformation, Ehlers-Danlos syndrome, X-linked external auditory canal atresia-dilated internal auditory canal-facial dysmorphism syndrome, joint laxity, short stature, and myopia, diaphragmatic malformation, abdominal wall malformation, port-wine nevi-mega cisterna magna-hydrocephalus syndrome, conjoined twins, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations

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

29 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 6 benign, 4 likely pathogenic, 3 conflicting classifications of pathogenicity, 3 pathogenic, 3 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686083	NM_001084.5(PLOD3):c.2061+1G>A	PLOD3	Pathogenic	criteria provided, single submitter
2159445	NM_001084.5(PLOD3):c.1354C>T (p.Arg452Ter)	PLOD3	Pathogenic	criteria provided, multiple submitters, no conflicts
225442	NM_001084.5(PLOD3):c.1890T>G (p.Tyr630Ter)	PLOD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6644	NM_001084.5(PLOD3):c.2071del (p.Cys691fs)	PLOD3	Pathogenic	no assertion criteria provided
3065547	NM_001084.5(PLOD3):c.1359-1G>C	PLOD3	Likely pathogenic	criteria provided, single submitter
3731304	NM_001084.5(PLOD3):c.2158G>T (p.Glu720Ter)	PLOD3	Likely pathogenic	criteria provided, single submitter
4795166	NM_001084.5(PLOD3):c.1359-1G>T	PLOD3	Likely pathogenic	criteria provided, single submitter
623469	NM_001084.5(PLOD3):c.809C>T (p.Pro270Leu)	PLOD3	Likely pathogenic	criteria provided, single submitter
1382324	NM_001084.5(PLOD3):c.1448C>T (p.Ser483Leu)	PLOD3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618838	NM_001084.5(PLOD3):c.1466C>T (p.Pro489Leu)	PLOD3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810156	NM_001084.5(PLOD3):c.335A>G (p.Asp112Gly)	PLOD3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033684	NM_001084.5(PLOD3):c.700G>A (p.Asp234Asn)	PLOD3	Uncertain significance	criteria provided, single submitter
1204488	NM_001084.5(PLOD3):c.670G>C (p.Gly224Arg)	PLOD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1487783	NM_001084.5(PLOD3):c.976G>A (p.Asp326Asn)	PLOD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1804992	NM_001084.5(PLOD3):c.889C>G (p.Arg297Gly)	PLOD3	Uncertain significance	criteria provided, single submitter
2435088	NM_001084.5(PLOD3):c.1381A>C (p.Ile461Leu)	PLOD3	Uncertain significance	criteria provided, single submitter
547022	NM_001084.5(PLOD3):c.887C>G (p.Pro296Arg)	PLOD3	Uncertain significance	criteria provided, multiple submitters, no conflicts
6643	NM_001084.5(PLOD3):c.668A>G (p.Asn223Ser)	PLOD3	Uncertain significance	criteria provided, single submitter
915354	NM_001084.5(PLOD3):c.1684C>T (p.Pro562Ser)	PLOD3	Uncertain significance	criteria provided, single submitter
440171	NM_001084.5(PLOD3):c.1977C>T (p.Asp659=)	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
440175	NM_001084.5(PLOD3):c.570C>T (p.Asp190=)	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
440176	NM_001084.5(PLOD3):c.1233-4G>A	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
440177	NM_001084.5(PLOD3):c.1179C>T (p.Ala393=)	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
440181	NM_001084.5(PLOD3):c.1935+105T>G	PLOD3	Likely benign	criteria provided, single submitter
440182	NM_001084.5(PLOD3):c.1144G>C (p.Asp382His)	PLOD3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
618835	NM_001084.5(PLOD3):c.1402C>G (p.Arg468Gly)	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
624295	NM_001084.5(PLOD3):c.1678G>C (p.Glu560Gln)	PLOD3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
717332	NM_001084.5(PLOD3):c.1986G>A (p.Pro662=)	PLOD3	Benign	criteria provided, multiple submitters, no conflicts
771160	NM_001084.5(PLOD3):c.1797G>A (p.Arg599=)	PLOD3	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
PLOD3	Strong	Autosomal recessive	bone fragility with contractures, arterial rupture, and deafness	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLOD3	Orphanet:300284	Connective tissue disorder due to lysyl hydroxylase-3 deficiency

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
PLOD3	HGNC:9083	ENSG00000106397	O60568	Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PLOD3	Multifunctional procollagen lysine hydroxylase and glycosyltransferase LH3	Multifunctional enzyme that catalyzes a series of essential post-translational modifications on Lys residues in procollagen.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLOD3	Enzyme (other)	yes	1.14.11.4	Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph

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
pancreatic ductal cell	1
stromal cell of endometrium	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLOD3	284	ubiquitous	marker	stromal cell of endometrium, pancreatic ductal cell, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLOD3	1,332

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLOD3	O60568	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Collagen biosynthesis and modifying enzymes	1	170.4×	0.006	PLOD3

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
protein O-linked glycosylation via galactose	1	16852.0×	7e-04	PLOD3
obsolete hydroxylysine biosynthetic process	1	5617.3×	0.001	PLOD3
epidermis morphogenesis	1	2808.7×	0.001	PLOD3
basement membrane assembly	1	1872.4×	0.002	PLOD3
endothelial cell morphogenesis	1	1053.2×	0.002	PLOD3
collagen biosynthetic process	1	1053.2×	0.002	PLOD3
lung morphogenesis	1	1053.2×	0.002	PLOD3
neural tube development	1	526.6×	0.003	PLOD3
vasodilation	1	366.4×	0.004	PLOD3
collagen fibril organization	1	224.7×	0.005	PLOD3
intracellular protein localization	1	104.7×	0.010	PLOD3
in utero embryonic development	1	72.0×	0.014	PLOD3

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
PLOD3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
PLOD3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PLOD3	1.14.11.4, 2.4.1.50, 2.4.1.66	procollagen-lysine 5-dioxygenase, procollagen galactosyltransferase, procollagen glucosyltransferase

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	1	PLOD3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PLOD3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.