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Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

1

Autosomal recessive HP:0000007

Biallelic PLOD3 variants. The first reported patient was a compound heterozygote; later families include homozygotes, among them a consanguineous family homozygous for c.809C>T p.(Pro270Leu).

Autosomal recessive inheritance

Show evidence (2 references)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance."

The original establishment of recessive inheritance, in the index compound heterozygote.

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"BCARD, linked to biallelic pathogenic variants in the PLOD3 gene, was characterized in 10 cases across six reports."

Confirms biallelic inheritance across the accumulated case literature.

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Discussions and Knowledge Gaps

5

How do collagen substrate, tissue and residual LH3 activity determine the human phenotype?

HUMAN MODEL MISMATCH plod3_collagen_specificity

Attached to

pathophysiology#Impaired Type IV and VI Collagen Secretion

Complete knockout markedly impairs type IV secretion in PFHR9 cells, while comparator fibroblasts retain type I/III secretion and a patient skin biopsy retains type IV immunostaining. These different readouts and systems do not support universal collagen secretion failure. Specific causal routes to hearing loss, retinal disease, bone fragility, cortical malformations and visceral anomalies remain incompletely resolved; organ expression alone does not establish those routes.

Show evidence (3 references)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture"

Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the staining for type IV collagen appeared unaltered as compared to control"

Full accepted manuscript of PMID:30463024: preserved type IV immunostaining in this patient limits extrapolation of the complete-knockout secretion defect to every human tissue.

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the secretion rates of fibrillar collagens α1α1α2(I) and α1α1α1(III) were comparable between WT and LH3 KO MEFs"

The fibroblast comparison demonstrates collagen- and model-dependent secretion effects.

Which patient alleles disrupt LH3-COLGALT1 assembly rather than catalytic activity or protein stability?

OPEN QUESTION plod3_complex_and_variant_effects

Attached to

pathophysiology#PLOD3 Biallelic Loss of Function

Direct assays and structures support distinct LH3 glucosyltransferase and COLGALT1 galactosyltransferase functions. Remaining uncertainty concerns allele-specific coupling and the physiological role of higher-order enzyme assemblies. Recombinant p.Pro270Leu could not be assayed reliably because protein yield was extremely low. Engineered substitutions at the LH3 interface, including Arg452, do not by themselves prove the mechanism of the patient Arg452_Val453 deletion.

Show evidence (2 references)

PMID:37446392 SUPPORT DIRECT PRIMARY RESULT In Vitro

"due to the almost non-detectable protein levels, we could not reliably carry out any in vitro investigations."

Recombinant p.Pro270Leu production was too low for reliable activity assays; this supports a stability concern but does not demonstrate selective loss of glucosyltransferase activity.

PMID:40069201 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The biological significance of KOGG’s linear polymerization remains unclear"

The structural study explicitly leaves the physiological higher-order assembly unresolved.

How much of BCARD reflects the post-Golgi pool of LH3?

OPEN QUESTION plod3_trafficking_versus_enzymatic_loss

Attached to

pathophysiology#PLOD3 Biallelic Loss of Function

VIPAR/VPS33B and sequential RAB10/RAB25 activity deliver LH3 to collagen-IV-containing carriers. ARC models and patients demonstrate collagen-modification abnormalities after trafficking defects, but ARC is not PLOD3-related BCARD. The relative contribution of ER and post-Golgi LH3 to BCARD has not been isolated by these studies.

Show evidence (2 references)

PMID:27435297 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"the N terminus of VIPAR as a novel indirect interactor of LH3"

The interaction is indirect; an intervening transmembrane partner was unresolved.

PMID:27435297 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"testing urine available from three different ARC patients with known mutations in VPS33B showed a substantial decrease in all LH3-dependent post-translational lysine modifications"

Reduced urinary collagen-modification products are not specific to PLOD3 deficiency.

Can the developmental zebrafish succinate response translate into treatment of human BCARD?

KNOWLEDGE GAP plod3_succinate_translation

Attached to

animal_models#mgtm635 plod3 Zebrafish

Early larval exposure improved body length and muscle geometry and shifted selected transcripts toward control levels. It did not establish human efficacy, safety, a measured succinate or ATP deficiency, post-onset rescue, or correction of established vascular and auditory complications. Increased autophagy markers may reflect adaptation or impaired turnover; inhibitor nonresponse does not resolve causality.

Show evidence (2 references)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"SA treatment significantly reduced the somite angle in treated animals by approximately 12%, trending towards WT levels"

The reported benefit is a developmental zebrafish endpoint.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Expression analysis of SA-treated animals by qPCR found no significant changes in transcript levels of plod3, and the UPR genes bip and ddit3"

The experiment did not demonstrate significant reversal of these UPR transcript readouts.

Are the candidate PLOD3 variants in isolated fetal intracranial hemorrhage causal?

KNOWLEDGE GAP plod3_fetal_hemorrhage_variants

Attached to

genetic#PLOD3

A 113-fetus study found no enrichment of rare predicted damaging PLOD3 variants. One fetus carried p.Leu198Pro alone and another carried p.Arg197Trp/p.Pro489Leu in trans; all three were ACMG class 3 in that report and had no patient functional validation. These findings do not establish dominant PLOD3 disease or count as confirmed BCARD cases.

Show evidence (2 references)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We did not find an enrichment of rare and predicted damaging PLOD3 qualifying variants between this cohort and the gnomAD control database"

The study had a negative burden comparison.

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Additional in vitro experiments are required to determine the causality of these variants"

The authors explicitly leave causality unresolved.

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Pathophysiology

11

PLOD3 Biallelic Loss of Function

Biallelic pathogenic variants can reduce LH3 abundance, stability and enzymatic activity. Human alleles need not selectively affect one catalytic function. The magnitude and combination of defects vary by allele and assay.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

procollagen glucosyltransferase activity GO:0033823 ↓ DECREASED procollagen-lysine 5-dioxygenase activity GO:0008475 ↓ DECREASED

Downstream

Reduced Collagen Hydroxylysine Glucosylation LH3 deficiency reduces glycosylated collagen hydroxylysine products.

Reduced Type IV Collagen Lysyl Hydroxylation Loss of LH3 decreases type IV collagen lysyl hydroxylation in knockout cells.

Show evidence (2 references)

PMID:30089812 SUPPORT DIRECT PRIMARY RESULT In Vitro

"LH3 N223S showed severely reduced lysyl hydroxylase and fully abolished glycosyltransferase activities"

Recombinant p.Asn223Ser impairs both activities; the study also found instability and degradation.

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient."

Patient tissue and cultured fibroblasts showed reduced LH3 protein.

Reduced Collagen Hydroxylysine Glucosylation

LH3 catalyzes addition of glucose to galactosyl-hydroxylysine. Direct mass-spectrometry assays assign the preceding galactose transfer to COLGALT1/GLT25D1. These enzymes form a 2:2 complex. Abnormal collagen glycosylation is supported by patient urinary products and by collagen analyses in knockout cells; it is not equivalent to loss of every sugar from every collagen. The process term includes elongation of a galactose-linked glycan; it does not assign the preceding galactose-transfer reaction to LH3.

Hydroxylysine-linked collagen glycosylation GO:0180062 ↓ DECREASED

Experimental models

Recombinant LH3-COLGALT1 Complex OTHER

Downstream

Impaired Type VI Collagen Tetramerization Loss of glycosylated hydroxylysines impairs intracellular type VI tetramer assembly.

Abnormal Type IV Collagen Triple Helix Reduced modification accompanies abnormal type IV triple-helix formation; the separate contribution of hydroxylation and glucosylation is unresolved.

Type VII Collagen Anchoring Fibril Disruption The PLOD3-deficient blistering patient had reduced type VII collagen and abnormal anchoring fibrils; direct biochemical proof of the intervening type VII modification defect is lacking.

Altered Extracellular Collagen Fibril Organization Reduced LH3-dependent modification accompanies abnormal extracellular fibrils in animal models; substrate-specific steps in humans remain unresolved.

Show evidence (3 references)

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine."

The full manuscript identifies urine as the assayed material, not patient tissue. Total hydroxylysine relative to lysine was preserved in this patient.

PMID:37446392 SUPPORT DIRECT PRIMARY RESULT In Vitro

"LH/PLOD enzymes are exclusively involved in the glucosylation of galactosyl hydroxylysines, whereas collagen galactosyltransferases, such as GLT25D1, are solely responsible for Hyl galactosylation."

Direct product assays distinguish collagen glucosylation from galactosylation.

PMID:40069201 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex"

Cryo-EM and recombinant complex assays support coordinated modification by distinct enzymes.

Reduced Type IV Collagen Lysyl Hydroxylation

LH3 knockout reduces hydroxylysines in type IV collagen in PFHR9 cells. Type I and III collagen hydroxylation was largely preserved in the comparator fibroblast model. Selective LH-deficient mice survive but develop structural matrix abnormalities.

peptidyl-lysine hydroxylation GO:0017185 ↓ DECREASED

Downstream

Abnormal Type IV Collagen Triple Helix Combined modification loss accompanies impaired helix formation; this experiment does not isolate the hydroxylation contribution.

Show evidence (2 references)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"more unmodified lysines (significantly fewer hydroxylysines), on COL4A1 and COL4A2 proteins isolated from LH3 KO PFHR9 cells"

Amino-acid analyses support reduced lysyl hydroxylation in type IV collagen in this knockout cell system.

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung."

Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.

Impaired Type VI Collagen Tetramerization

In LH3-null embryos and cultured cells, deficient hydroxylysine glycosylation impairs intracellular type VI collagen tetramerization. This model result is not a demonstrated uniform block in all patient tissues.

Downstream

Impaired Type IV and VI Collagen Secretion Defective intracellular assembly is associated with impaired secretion of highly glycosylated collagens.

Show evidence (1 reference)

PMID:17873278 SUPPORT DIRECT PRIMARY RESULT Model Organism

"loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens"

Knockout embryos and cultured cells link altered collagen glycosylation with defective type VI assembly and impaired secretion.

Abnormal Type IV Collagen Triple Helix

Type IV collagen isolated from LH3-knockout PFHR9 cells lacked a stable normal triple helix, showed altered HSP47 binding and failed to form normal higher-order assemblies. HSP47 binding was reduced or altered, rather than absent.

Downstream

Impaired Type IV and VI Collagen Secretion Abnormal collagen maturation accompanies delayed export in knockout cells.

Show evidence (1 reference)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"collagen α1α1α2(IV) produced by LH3 KO cells did not form stable triple helical helices"

Purified type IV collagen from knockout PFHR9 cells had abnormal circular-dichroism spectra and altered oligomerization.

Impaired Type IV and VI Collagen Secretion

Secretion of type IV and VI collagen is impaired in LH3-deficient experimental systems. Type IV export remains detectable even in complete-knockout PFHR9 cells, and type I/III secretion was largely preserved in comparator fibroblasts. Human skin can retain normal type IV staining.

protein secretion GO:0009306 ↓ DECREASED

Experimental models

LH3-Knockout PFHR9 Cells CELL LINE

Downstream

Basement Membrane Disorganization Abnormal type IV localization compromises basement membrane assembly in the mouse model.

Collagen Retention in the Endoplasmic Reticulum Reduced collagen handling is associated with intracellular retention; the patient-cell result concerns type I collagen.

Show evidence (3 references)

PMID:17873278 SUPPORT DIRECT PRIMARY RESULT Model Organism

"loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens"

Knockout embryos and cultured cells link altered collagen glycosylation with defective type VI assembly and impaired secretion.

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture"

Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the staining for type IV collagen appeared unaltered as compared to control"

Full accepted manuscript of PMID:30463024: preserved type IV immunostaining in this patient limits extrapolation of the complete-knockout secretion defect to every human tissue.

Basement Membrane Disorganization

LH3-deficient mice show abnormal basement membrane structure and type IV collagen distribution. The human blistering case had fragmented lamina densa but preserved type IV staining, indicating that matrix integrity cannot be inferred from staining abundance alone.

basement membrane GO:0005604

Animal models

LH3 Activity-Selective and Hypomorphic Mice Mus musculus partially recapitulates

Show evidence (4 references)

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5"

Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung."

Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the staining for type IV collagen appeared unaltered as compared to control"

Full accepted manuscript of PMID:30463024: preserved type IV immunostaining in this patient limits extrapolation of the complete-knockout secretion defect to every human tissue.

+ 1 more reference

Altered Extracellular Collagen Fibril Organization

Selective hydroxylase-deficient mice show disorganized fibrils, and mutant zebrafish cartilage has sparse extracellular collagen fibrils. These findings support a matrix-organization defect, while the contribution of individual collagen substrates to human bone fragility remains unresolved.

collagen fibril organization GO:0030199 ⚠ ABNORMAL

Animal models

LH3 Activity-Selective and Hypomorphic Mice Mus musculus partially recapitulates

mgtm635 plod3 Zebrafish Danio rerio partially recapitulates

Show evidence (2 references)

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung."

Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"surrounded by sparse extracellular matrix lacking collagen fibrils"

Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.

Type VII Collagen Anchoring Fibril Disruption

The p.Leu627Pro patient had reduced type VII collagen, variable anchoring-fibril density and morphology, and sub-lamina-densa cleavage. Some areas retained normal-looking fibrils. Negative testing across epidermolysis-bullosa genes and PLOD3 functional findings support this association without making negative COL7A1 testing alone proof of causality.

Downstream

Abnormal blistering of the skin The abnormal anchoring-fibril system is associated with separation below the lamina densa.

Show evidence (1 reference)

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced."

Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.

Collagen Retention in the Endoplasmic Reticulum

Patient-derived fibroblasts carrying the splice-altering c.1354C>T allele show collagen I colocalization with ER markers and distended ER. Mutant zebrafish chondrocytes accumulate collagen II intracellularly, although extracellular collagen II remains detectable.

fibroblast CL:0000057

endoplasmic reticulum GO:0005783

Experimental models

Patient-Derived PLOD3 Dermal Fibroblasts PRIMARY CELL CULTURE

Downstream

PERK Branch Unfolded Protein Response Collagen retention and ER distension accompany PERK-branch activation; the sequence is supported by paired model readouts rather than a selective retention intervention.

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"COL1 (red) staining partially co-localized with ERp57 (ER marker; green)"

Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.

PERK Branch Unfolded Protein Response

Mutant zebrafish and patient fibroblast studies show ER stress with increased PERK-branch readouts. The data do not establish this response as the cause of organ damage; inhibitor experiments did not rescue the zebrafish phenotype and the authors proposed an adaptive role.

PERK-mediated unfolded protein response GO:0036499 ↑ INCREASED

Animal models

mgtm635 plod3 Zebrafish Danio rerio partially recapitulates

Show evidence (2 references)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish"

The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Comparative TEM and immunoblot analyses in the patient’s fibroblasts confirmed these findings"

The patient-cell comparison also showed distended ER and corresponding stress-response protein changes.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

41

Blood 2

Easy bruising Bruising susceptibility HP:0000978

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Bruising occurred readily but prothrombin and partial thromboplastin times and platelet counts were all found to be normal."

Reported human clinical finding; no disease-wide frequency is inferred.

Cerebral hemorrhage HP:0001342

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"a spontaneous cerebral arterial haemorrhage presented with hemiplegia."

Reported human clinical finding; no disease-wide frequency is inferred.

Cardiovascular 4

Arterial dissection HP:0005294

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"risk of arterial rupture due to vascular aneurisms or dissections"

The vascular feature as stated in the syndrome definition. Quoted including the source's spelling "aneurisms", since a snippet reproduces its source.

Abnormal heart morphology HP:0001627

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports minor cardiac anomalies. Bound to the generic heart-morphology term because the source characterises them as minor without naming a lesion.

Popliteal Artery Aneurysm Vascular dilatation HP:0002617

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A spontaneous rupture of a right popliteal aneurysm ... presented with pain and swelling."

Direct clinical documentation of a ruptured peripheral arterial aneurysm.

Carotid Artery Dilatation HP:0012163

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A subsequent CT scan when the patient was 14 years of age demonstrated gross dilatation of both internal carotids"

The documented carotid lesion is recorded separately from the ruptured popliteal aneurysm.

Digestive 1

Abnormal intestine morphology HP:0002242

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports an intestinal anomaly. Bound to the generic intestinal-morphology term because the source names no specific lesion.

Ear 2

Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"sensorineural hearing loss, reduced palmar creases, finger contractures"

Names sensorineural hearing loss among the collated key features.

Low-set ears HP:0000369

Show evidence (1 reference)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Dysmorphic features included hypertelorism, an upturned nose, and low‐set ears"

The neurologic case provides a specific facial finding rather than only a coarse dysmorphism label.

Eye 6

Cataract HP:0000518

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"characterized by bone abnormalities, cataract, risk of arterial rupture due to vascular aneurisms or dissections, and sensorineural deafness"

The syndrome definition, which names cataract as a cardinal feature.

Retinal detachment HP:0000541

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"ocular abnormalities with risk for retinal detachment"

Names the retinal detachment risk directly.

High myopia HP:0011003

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The patient was born with a right eye cataract, ptosis, severe myopia"

Full accepted manuscript of PMID:30463024 explicitly identifies severe myopia.

Ptosis HP:0000508

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmologic surgery to correct unilateral ptosis was performed at 10 months of age."

Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.

Strabismus HP:0000486

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmologic examination showed amblyopia and strabismus, in addition to his neonatal ophthalmologic findings"

Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.

Amblyopia HP:0000646

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmologic examination showed amblyopia and strabismus, in addition to his neonatal ophthalmologic findings"

Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.

Genitourinary 1

Vesicoureteral reflux HP:0000076

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports vesico-ureteral reflux in the patient whose case expanded the phenotype.

Head and Neck 4

Abnormal facial shape HP:0001999

Coarse binding: source unspecified

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection"

Names the craniofacial dysmorphism among the collated key features.

Microcephaly HP:0000252

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT BACKGROUND Human Clinical

"developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis"

Reported human clinical finding; no disease-wide frequency is inferred.

Midface retrusion HP:0011800

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT BACKGROUND Human Clinical

"developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis"

Reported human clinical finding; no disease-wide frequency is inferred.

Micrognathia HP:0000347

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT BACKGROUND Human Clinical

"developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis"

Reported human clinical finding; no disease-wide frequency is inferred.

Integument 6

Abnormal palmar crease morphology HP:0010490

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"sensorineural hearing loss, reduced palmar creases, finger contractures"

Names the reduced palmar creases among the collated key features.

Abnormal blistering of the skin HP:0008066

Show evidence (2 references)

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced."

Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Blistering affecting all toes and fingers and blistering of the pinnae was present"

The founding patient also had skin blistering, which healed without scarring.

Thin skin HP:0000963

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The skin appeared to be thin and poorly perfused but with no significant abnormalities of healing or scarring."

Reported human clinical finding; no disease-wide frequency is inferred.

Nail hypoplasia Small nail HP:0001792

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"All nails were hypoplastic, although the small, dysplastic fingernails were described as “rapidly-growing with brittle tips”"

Reported human clinical finding; no disease-wide frequency is inferred.

Multiple pterygia HP:0001040

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He had pterygia of the neck, axilla, antecubital, popliteal, digital and intercrural areas."

Full accepted manuscript of PMID:30463024 documents the distribution.

Poor wound healing HP:0001058

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"trauma-induced skin blisters over the prominent body areas, particularly on elbows, feet, knees, and ears with history of delayed wound healing"

Full accepted manuscript of PMID:30463024 reports delayed wound healing.

Limbs 1

Talipes equinovarus HP:0001762

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skeletal problems included bilateral talipes equinovarus requiring surgical correction"

Reported human clinical finding; no disease-wide frequency is inferred.

Musculoskeletal 6

Reduced bone mineral density HP:0004349

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular..."

The collated feature list from the review that proposed the diagnostic label.

Joint contracture HP:0034392

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"finger contractures, prominent knees, scoliosis"

Names the contractures among the collated key features.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"prominent knees, scoliosis, low bone mineral density"

Names scoliosis among the collated key features.

Recurrent fractures HP:0002757

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Osteopenia and healed fractures of the left clavicle, right femur, and right humerus were seen."

Reported human clinical finding; no disease-wide frequency is inferred.

Platyspondyly HP:0000926

Show evidence (1 reference)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The vertebrae were flattened, and the lower and upper edges were slightly concave."

Reported human clinical finding; no disease-wide frequency is inferred.

Diaphragmatic eventration HP:0009110

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"A right-sided diaphragmatic eventration was repaired when the patient was 5 months of age."

Reported human clinical finding; no disease-wide frequency is inferred.

Nervous System 6

Global developmental delay HP:0001263

Show evidence (2 references)

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"craniofacial dysmorphisms, developmental delay and risk for vascular dissection"

Names developmental delay among the collated key features.

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Development was globally delayed. She walked independently at 4 years of age."

Direct clinical documentation of global delay in the founding patient.

Focal-onset seizure HP:0007359

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports focal epilepsy in the patient whose case expanded the phenotype.

Polymicrogyria HP:0002126

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports polymicrogyria among the brain abnormalities in the expanded phenotype.

Gray matter heterotopia HP:0002282

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"

Reports heterotopia. Bound to the generic gray-matter-heterotopia term because the source does not specify its distribution.

Infantile spasms HP:0012469

Show evidence (1 reference)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"At 8 months of age, she presented with clustered epileptic spasms."

Reported human clinical finding; no disease-wide frequency is inferred.

Hypsarrhythmia HP:0002521

Show evidence (1 reference)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The imaging features of the patient were consistent with the diagnosis of cerebral SVD. Electroencephalography (EEG) suggested hypsarrhythmia."

Reported human clinical finding; no disease-wide frequency is inferred.

Growth 2

Intrauterine growth retardation HP:0001511

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Pregnancy was complicated by intrauterine growth retardation (IUGR)."

Reported human clinical finding; no disease-wide frequency is inferred.

Short stature HP:0004322

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Postnatally, growth continued below −2 standard deviations."

Reported human clinical finding; no disease-wide frequency is inferred.

🧬

Genetic Associations

1

PLOD3

Gene: PLOD3 hgnc:9083 relationship_type: CAUSATIVE

Show evidence (8 references)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance."

The founding patient established biallelic PLOD3-related disease.

PMID:31129566 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant"

The three individuals belonged to one family, rather than three independent families.

PMID:37446392 SUPPORT DIRECT PRIMARY RESULT In Vitro

"due to the almost non-detectable protein levels, we could not reliably carry out any in vitro investigations."

Recombinant p.Pro270Leu production was too low for reliable activity assays; this supports a stability concern but does not demonstrate selective loss of glucosyltransferase activity.

+ 5 more references

🗃️

External Assertions

1

OMIM bone fragility with contractures, arterial rupture, and deafness record

OMIM disease record OMIM:612394

OMIM phenotype record for the PLOD3-related recessive connective tissue disorder.

💊

Medical Actions

8

Vascular Surveillance

Action: Supportive Care NCIT:C15747

Platform: Other

Monitor for arterial aneurysm and dissection in a specialist setting. The case-series authors recommend early recognition and monitoring; no comparative outcome study or validated surveillance interval establishes its benefit in BCARD.

Show evidence (1 reference)

PMID:31129566 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes."

The authors recommend monitoring to reduce ocular and vascular morbidity; this is a proposed benefit, not a measured treatment effect.

Ophthalmologic Surveillance

Action: Supportive Care NCIT:C15747

Platform: Other

Ophthalmologic follow-up addresses cataract, refractive error and retinal detachment risk. Recommendations arise from the clinical spectrum and expert interpretation of small case series.

Show evidence (1 reference)

PMID:31129566 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes."

The authors recommend monitoring to reduce ocular and vascular morbidity; this is a proposed benefit, not a measured treatment effect.

Cochlear Implantation

Action: Surgical Procedure NCIT:C15329

Platform: Device

Profound bilateral sensorineural deafness was treated with cochlear implantation in the founding patient. The report does not quantify hearing improvement.

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"was treated with cochlear implantation."

The original case reports an actual audiologic intervention, without a quantified postoperative outcome.

Orthopedic Surgery

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Bilateral clubfoot required surgical correction in the founding patient. Treatment of skeletal abnormalities is individualized; this report does not establish a bone-directed drug regimen.

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Skeletal problems included bilateral talipes equinovarus requiring surgical correction"

Directly documented orthopedic intervention.

Ocular Surgery

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

Cataracts required surgery at seven years in the founding patient, and unilateral ptosis was corrected at ten months in the p.Leu627Pro child. These are reported interventions, not comparative efficacy estimates.

Show evidence (2 references)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"cataracts requiring surgery at age 7 of the patient"

Cataract surgery was documented in the original case.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Ophthalmologic surgery to correct unilateral ptosis was performed at 10 months of age."

Full accepted manuscript of PMID:30463024 documents ptosis correction.

Repair of Symptomatic Diaphragmatic Eventration

Action: Surgical Procedure NCIT:C15329

Platform: Surgery

The founding patient required two repairs after the initial repair failed in a friable diaphragm. The p.Leu627Pro child improved without intervention, so surgery is not uniformly required.

Show evidence (2 references)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The diaphragm was noted to be friable; the initial repair failed and a second surgical repair was needed."

The report describes operative failure followed by repeat repair.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Diaphragmatic eventration disappeared with aging without intervention."

Full accepted manuscript of PMID:30463024 documents spontaneous improvement in a different child.

Treatment of Infantile Spasms

Action: Pharmacotherapy NCIT:C15986

Agent: corticotropin CHEBI:3892 topiramate CHEBI:63631 sodium valproate CHEBI:9925 nitrazepam CHEBI:7581 vigabatrin CHEBI:63638

Platform: Other

In the p.Leu406del child, two weeks of ACTH did not reduce spasms. Subsequent topiramate, valproate, nitrazepam and vigabatrin reduced frequency by no more than half, with persistent spasms at fourteen months. A ketogenic diet was suggested but no response was reported. These observations describe one refractory case.

Show evidence (3 references)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"but seizure frequency did not change. Multiple antiepileptic drugs (AEDs) were added"

The child did not respond to the reported ACTH course; additional drugs were then introduced.

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The seizure frequency was reduced by no more than 50%."

Incomplete response after multidrug treatment in a single case.

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Adrenocorticotrophic hormone ... was administered for two consecutive weeks ... Multiple antiepileptic drugs (AEDs) were added, including topiramate ... sodium valproate ... nitrazepam ... and vigabatrin"

The report identifies ACTH followed by these four antiseizure drugs; it does not isolate a response to each agent.

Genetic Counseling and Family Testing

Action: Genetic Counseling NCIT:C15240

Discuss autosomal recessive inheritance and test relatives for the familial alleles. When both parents are heterozygous carriers, Mendelian recurrence is one in four per pregnancy. RNA or functional studies may be needed to interpret splice-altering or otherwise uncertain variants.

Show evidence (1 reference)

PMID:18834968 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Our restriction analysis indicated that mutation 1 was inherited from the father and mutation 2 was inherited from the mother"

Parental segregation supports recessive counseling; the recurrence fraction follows Mendelian inheritance, not an observed cohort rate.

🔬

Biochemical Markers

1

Reduced urinary glycosylated hydroxylysine (PRESENT)

Pathograph Readouts

Readout Of Reduced Collagen Hydroxylysine Glucosylation Negative

Reduced glycosylated hydroxylysine products reflect defective collagen modification, but do not isolate every enzyme step or establish diagnostic specificity.

Show evidence (1 reference)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the ratio of (GGHL + GHL)/HL in the proband was reduced to about 17% of that measured in his parents"

Full accepted manuscript of PMID:30463024: urinary glycosylated hydroxylysine relative to hydroxylysine was about 17% of parental values. This is a single-family functional observation, not a validated diagnostic cutoff.

Show evidence (2 references)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the ratio of (GGHL + GHL)/HL in the proband was reduced to about 17% of that measured in his parents"

Full accepted manuscript of PMID:30463024: urinary glycosylated hydroxylysine relative to hydroxylysine was about 17% of parental values. This is a single-family functional observation, not a validated diagnostic cutoff.

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine."

The full manuscript identifies urine as the assayed material, not patient tissue. Total hydroxylysine relative to lysine was preserved in this patient.

🔬

Diagnosis

5

Biallelic PLOD3 Molecular Diagnosis

Sequence PLOD3 in a patient with compatible connective tissue features, using a panel or exome/genome approach as appropriate, and establish segregation of candidate alleles. A rare variant or computational prediction alone does not confirm BCARD.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3)."

Documents the molecular route in the blistering patient.

RNA Analysis of Suspected Splice-Altering Variants

Transcript analysis can establish an unexpected splice consequence, including an in-frame deletion instead of a predicted stop-gain product. Results need interpretation in the assayed tissue and alongside phenotype and segregation.

Show evidence (2 references)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The first variant functions as a cryptic splice site variant, and RNA analysis confirmed that it causes a 4 bp truncation of exon 3."

The reported c.335A>G allele acts through aberrant splicing; the resulting frameshift is p.Asp112AlafsTer4.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the c.1354 C > T transition created a premature GT splice donor site leading to a 6-bp in frame deletion"

Patient-derived RNA showed an in-frame deletion affecting Arg452 and Val453; a predicted stop-gain annotation does not describe the observed transcript.

Collagen Modification and LH3 Protein Studies

Urinary collagen-derived hydroxylysine glycosides and pyridinoline products, or LH3 protein measurements in patient-derived cells, can support a functional defect. Availability is limited and validated BCARD diagnostic thresholds are not established. Reduced glycosylation products can also occur in ARC syndrome.

Show evidence (2 references)

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf SUPPORT DIRECT PRIMARY RESULT Human Clinical

"the ratio of (GGHL + GHL)/HL in the proband was reduced to about 17% of that measured in his parents"

Full accepted manuscript of PMID:30463024: urinary glycosylated hydroxylysine relative to hydroxylysine was about 17% of parental values. This is a single-family functional observation, not a validated diagnostic cutoff.

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Western blotting showed markedly reduced levels of LH3 in the patient"

Patient fibroblasts showed reduced LH3; urine pyridinoline and enzyme activity were not measured in this case.

Skin Ultrastructure in Blistering Presentations

Sub-lamina-densa cleavage, abnormal anchoring fibrils and reduced type VII collagen can resemble COL7A1-related dystrophic epidermolysis bullosa. Molecular testing and the multisystem presentation determine the diagnosis; immunostaining alone is not PLOD3-specific.

Show evidence (1 reference)

PMID:30463024 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced."

Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.

Neuroimaging and EEG for Neurologic Presentations

MRI and EEG characterized bleeding foci, white-matter abnormalities, cerebral atrophy and hypsarrhythmia in the p.Leu406del child. Normal MRA/MRV did not exclude the imaging-based small-vessel phenotype. This is diagnostic characterization of a symptomatic case, not a universal screening protocol.

Show evidence (1 reference)

PMID:36203519 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The imaging features of the patient were consistent with the diagnosis of cerebral SVD. Electroencephalography (EEG) suggested hypsarrhythmia."

MRI supported small-vessel involvement and EEG identified the epileptic pattern; no vascular biopsy established the mechanism.

📊

Prevalence

1

Worldwide, reported cases

Cases In Literature

The 2025 report described ten previously published cases across six reports and added an 11-year-old girl. This is a dated literature count, not a population prevalence or a current total.

Show evidence (1 reference)

PMID:40289369 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"was characterized in 10 cases across six reports"

The published case count, which is the only occurrence figure available.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Bone Fragility With Contractures Arterial Rupture And Deafness:

Stickler Syndrome

Overlapping Features Ocular, auditory and skeletal features overlap.

Distinguishing Features

PLOD3-related disease can add arterial rupture, skin blistering, nail abnormalities and prenatal growth restriction; molecular testing resolves the overlap.

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"By contrast, growth retardation, nail and skin abnormalities, osteopenia, joint contractures, and spontaneous vascular rupture are not seen in Stickler syndrome."

The founding report discusses features differentiating that patient from the then-recognized Stickler spectrum; the comparison is source-specific.

Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome

Overlapping Features VPS33B/VIPAS39 defects impair LH3 trafficking and can reduce collagen glycosylation products, creating biochemical and connective tissue overlap.

Distinguishing Features

Renal dysfunction, cholestasis and platelet alpha-granule defects point toward ARC; PLOD3-related BCARD has a different molecular cause.

Show evidence (1 reference)

PMID:27435297 SUPPORT INDIRECT BACKGROUND Human Clinical

"ARC syndrome caused by VPS33B or VIPAR deficiencies results in abnormal kidney and liver function, extremely dry skin (ichthyosis), defective platelet α-granule biogenesis, osteopaenia and recurrent bone fractures"

The trafficking study defines the clinically distinct ARC context.

Bruck Syndrome

Overlapping Features Bone fragility with contractures overlaps with PLOD3 disease.

Distinguishing Features

The broader ocular, auditory, skin and vascular phenotype can suggest BCARD; PLOD2-related Bruck syndrome affects a different collagen-modifying enzyme.

Show evidence (1 reference)

PMID:18834968 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Although osteopenia is a feature of EDS VI, caused by PLOD1 mutations, associated fractures are more in keeping with Bruck syndrome ... caused by PLOD2 mutations"

The founding report discusses Bruck syndrome in the differential.

🧫

Experimental Models

3

LH3-Knockout PFHR9 Cells CELL_LINE

CRISPR disruption of Plod3 exons 5 and 7 in a collagen-IV-producing cell line reveals reduced type IV hydroxylation/glucosylation, abnormal triple helices and delayed secretion. Comparator commercial embryonic fibroblasts retained largely normal type I/III secretion despite decreased glucosylation.

Organism

Mus musculus NCBITaxon:10090

Cell source

Murine PFHR9 cell line, ATCC CRL-2423

Publication

PMID:36403858

Pathograph links

Impaired Type IV and VI Collagen Secretion partially recapitulates

Limitations: The experiment directly addresses type IV collagen in a murine cell line with high collagen-IV production, not every collagen or patient tissue.

Show evidence (1 reference)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture"

Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.

Show evidence (3 references)

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"more unmodified lysines (significantly fewer hydroxylysines), on COL4A1 and COL4A2 proteins isolated from LH3 KO PFHR9 cells"

Amino-acid analyses support reduced lysyl hydroxylation in type IV collagen in this knockout cell system.

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"collagen α1α1α2(IV) produced by LH3 KO cells did not form stable triple helical helices"

Purified type IV collagen from knockout PFHR9 cells had abnormal circular-dichroism spectra and altered oligomerization.

PMID:36403858 SUPPORT DIRECT PRIMARY RESULT In Vitro

"only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture"

Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.

Patient-Derived PLOD3 Dermal Fibroblasts PRIMARY_CELL_CULTURE

Patient fibroblasts were compared with unrelated BJ controls. RNA analysis identified p.Arg452_Val453del. Collagen I retention, distended ER, stress-response and autophagy-associated markers, and mitochondrial ultrastructural abnormalities were observed. The study did not use an isogenic corrected patient line or measure respiratory flux.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Dermal biopsy-derived fibroblasts carrying c.1354C>T with an in-frame splice product

Publication

PMID:41827019

Pathograph links

Collagen Retention in the Endoplasmic Reticulum partially recapitulates

Limitations: A single patient-derived line with an unrelated control limits attribution of every difference to the variant.

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"COL1 (red) staining partially co-localized with ERp57 (ER marker; green)"

Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.

Show evidence (3 references)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"COL1 (red) staining partially co-localized with ERp57 (ER marker; green)"

Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"the c.1354 C > T transition created a premature GT splice donor site leading to a 6-bp in frame deletion"

Patient-derived RNA showed an in-frame deletion affecting Arg452 and Val453; a predicted stop-gain annotation does not describe the observed transcript.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT In Vitro

"primary, patient-derived fibroblasts cultured under basal conditions showed a highly significant increase in ATG5, P62, LC3-I and LC3-II, and LAMP1"

Patient-derived fibroblasts also had increased autophagy-associated proteins. These marker levels do not prove increased degradative flux.

Recombinant LH3-COLGALT1 Complex OTHER

Purified recombinant proteins, cryo-EM and enzymatic assays define a 2:2 LH3-COLGALT1 complex and separate hydroxylase, galactosyltransferase and glucosyltransferase functions. Engineered interface substitutions can impair complex formation; this does not directly establish the effect of each patient allele.

Organism

Homo sapiens NCBITaxon:9606

Publication

PMID:40069201

Pathograph links

Reduced Collagen Hydroxylysine Glucosylation measures

Limitations: Wild-type and engineered recombinant systems define the normal machinery; variant-specific effects require direct testing.

Show evidence (1 reference)

PMID:40069201 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex"

Cryo-EM and recombinant complex assays support coordinated modification by distinct enzymes.

Show evidence (2 references)

PMID:40069201 SUPPORT DIRECT PRIMARY RESULT In Vitro

"The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex"

The structural system identifies the multienzyme assembly.

PMID:40240392 SUPPORT DIRECT PRIMARY RESULT In Vitro

"GLT25D1/COLGALT1 dimerization critically contributes to macromolecular complex formation with multifunctional LH3/PLOD3 enzymes."

An independent structural and cross-linking study supports the complex interface.

🐁

Animal Models

2

LH3 Activity-Selective and Hypomorphic Mice

A hydroxylase-selective mutant develops but has basement-membrane and fibril defects. Reduced glucosyltransferase activity in a hypomorphic line causes embryonic lethality at E9.5–14.5; survival tracks residual activity. These manipulations do not reproduce the mixed effects of every human allele.

Species

Mus musculus

Publication

PMID:16467571

Pathograph links

Basement Membrane Disorganization partially recapitulates

Limitations: Embryonic mouse matrix failure differs from the variable, survivable human syndrome.

Show evidence (1 reference)

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5"

Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.

Altered Extracellular Collagen Fibril Organization partially recapitulates

Limitations: Selective hydroxylase loss remains pathogenic to matrix structure despite survival.

Show evidence (1 reference)

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung."

Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.

Show evidence (2 references)

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung."

Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.

PMID:16467571 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5"

Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.

mgtm635 plod3 Zebrafish

An ENU-derived missense model shows craniofacial, musculoskeletal, vascular, eye and ear abnormalities and early larval lethality. CRISPR exon-4 disruption phenocopies key defects. Human wild-type PLOD3 mRNA injected at the one-cell stage partially rescues the phenotype; tested clinical constructs have variable residual rescue. Autophagy-associated proteins and compartments increase, but these readouts do not by themselves quantify autophagic flux. Mitochondrial structural abnormalities and reduced metabolic transcripts do not establish a measured ATP deficit.

Species

Danio rerio

Genotype

Homozygous plod3 p.Gly245Glu (mgtm635)

Publication

PMID:41827019

Pathograph links

Altered Extracellular Collagen Fibril Organization partially recapitulates

Limitations: Early developmental cartilage model with severe larval disease; human tissue specificity and natural history differ.

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"surrounded by sparse extracellular matrix lacking collagen fibrils"

Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.

PERK Branch Unfolded Protein Response partially recapitulates

Limitations: The stress response is measured; its role as harmful or adaptive is not resolved.

Show evidence (1 reference)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish"

The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.

Succinate at 200 micromolar in egg water from 10 hours post-fertilization to four days improved body length and somite angle, with the angle reduced about 12%. Three metabolic transcripts approached wild-type levels; UPR transcript changes were not significant. This developmental experiment provides no human efficacy or safety evidence.

Show evidence (5 references)

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"surrounded by sparse extracellular matrix lacking collagen fibrils"

Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish"

The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.

PMID:41827019 SUPPORT DIRECT PRIMARY RESULT Model Organism

"wild-type human PLOD3 mRNA partially rescued musculoskeletal, vascular, and brain phenotypes in zebrafish plod3 mutants"

Developmental mRNA rescue supports conservation of PLOD3 function; it is not evidence of human gene therapy.

+ 2 more references

{ }

Source YAML

click to show

name: Bone Fragility With Contractures Arterial Rupture And Deafness
category: Mendelian
creation_date: "2026-09-14T00:00:00Z"
synonyms:
- BCARD syndrome
- lysyl hydroxylase 3 deficiency
- LH3 deficiency
- PLOD3-related connective tissue disorder
description: >-
  BCARD is an autosomal recessive multisystem connective tissue disorder caused by biallelic pathogenic PLOD3
  variants affecting lysyl hydroxylase 3 (LH3). Skeletal fragility and contractures, cataracts or other ocular
  abnormalities, sensorineural hearing loss, and arterial complications occur in variable combinations. Skin
  blistering, developmental delay, and neurologic or visceral abnormalities broaden the phenotype. LH3 contributes
  both collagen lysine hydroxylation and hydroxylysine glucosylation, working with the galactosyltransferase
  COLGALT1. Patient studies demonstrate reduced LH3 abundance or activity and abnormal urinary collagen glycosylation
  products. Experimental loss of LH3 impairs collagen assembly, secretion, and extracellular matrix organization
  in a collagen- and model-dependent manner. Selective mouse experiments establish an essential developmental
  role for glucosyltransferase activity, while also showing structural defects after loss of hydroxylase activity.
  Human alleles can affect both functions. Management addresses documented complications and includes ocular
  and vascular monitoring; the small case literature does not establish phenotype frequencies or treatment-effect
  estimates.
disease_term:
  preferred_term: bone fragility with contractures, arterial rupture, and deafness
  term:
    id: MONDO:0012892
    label: bone fragility with contractures, arterial rupture, and deafness
parents:
- Connective Tissue Disease
references:
- reference: PMID:16467571
  title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
- reference: PMID:17873278
  title: Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
- reference: PMID:18834968
  title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
- reference: PMID:27435297
  title: Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
- reference: PMID:30089812
  title: Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3.
- reference: PMID:30463024
  title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
- reference: PMID:31129566
  title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
- reference: PMID:36203519
  title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
- reference: PMID:36403858
  title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
- reference: PMID:37446392
  title: Identification of Regulatory Molecular "Hot Spots" for LH/PLOD Collagen Glycosyltransferase Activity.
- reference: PMID:40069201
  title: The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.
- reference: PMID:40240392
  title: Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1.
- reference: PMID:40289369
  title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
- reference: PMID:41827019
  title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
- reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
  title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
inheritance:
- name: Autosomal recessive
  description: >-
    Biallelic PLOD3 variants. The first reported patient was a compound heterozygote; later
    families include homozygotes, among them a consanguineous family homozygous for
    c.809C>T p.(Pro270Leu).
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance."
    explanation: The original establishment of recessive inheritance, in the index compound heterozygote.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BCARD, linked to biallelic pathogenic variants in the PLOD3 gene, was characterized in 10 cases across six reports."
    explanation: Confirms biallelic inheritance across the accumulated case literature.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
genetic:
- name: PLOD3
  gene_term:
    preferred_term: PLOD3
    term:
      id: hgnc:9083
      label: PLOD3
  relationship_type: CAUSATIVE
  notes: >-
    PLOD3 encodes LH3, with an N-terminal glucosyltransferase domain, an accessory domain, and a C-terminal
    lysyl hydroxylase domain. Reported alleles include compound heterozygous p.Asn223Ser/p.Cys691AlafsTer9,
    homozygous p.Leu627Pro, p.Pro270Leu and p.Leu406del, and the 2025 c.335A>G/c.2158G>T pair. The first pair
    affects both enzyme functions and protein abundance, rather than selectively separating them. RNA analysis
    is important: c.335A>G produces a four-base exon-3 truncation and frameshift; in a 2026 patient fibroblast
    study, c.1354C>T produced an in-frame p.Arg452_Val453del transcript rather than the predicted p.Arg452Ter
    product. Residual function and clinical severity cannot be assigned from domain position alone.
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: We report here a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance.
    explanation: The founding patient established biallelic PLOD3-related disease.
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: three further individuals from a consanguineous family with a homozygous PLOD3 c.809C>T; p.(Pro270Leu) variant
    explanation: The three individuals belonged to one family, rather than three independent families.
  - reference: PMID:37446392
    reference_title: Identification of Regulatory Molecular "Hot Spots" for LH/PLOD Collagen Glycosyltransferase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: due to the almost non-detectable protein levels, we could not reliably carry out any in vitro investigations.
    explanation: Recombinant p.Pro270Leu production was too low for reliable activity assays; this supports a stability concern but does not demonstrate selective loss of glucosyltransferase activity.
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient carried a homozygous variant of c.1216_1218delCTC (p.L406del) in PLOD3, which was inherited from her heterozygous parents.
    explanation: Segregation of the in-frame deletion in the child with small-vessel imaging abnormalities and infantile spasms.
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The first variant functions as a cryptic splice site variant, and RNA analysis confirmed that it causes a 4 bp truncation of exon 3.
    explanation: The reported c.335A>G allele acts through aberrant splicing; the resulting frameshift is p.Asp112AlafsTer4.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the c.1354 C > T transition created a premature GT splice donor site leading to a 6-bp in frame deletion
    explanation: Patient-derived RNA showed an in-frame deletion affecting Arg452 and Val453; a predicted stop-gain annotation does not describe the observed transcript.
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: c.1880T>C; p.Leu627Pro, and this was confirmed by bidirectional Sanger sequencing
    explanation: Full accepted manuscript of PMID:30463024 identifies the homozygous missense allele; both parents were heterozygous carriers.
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mutation 2 resulted in complete loss of the LH activity for LH3, as well as reduced its GT and GGT activities.
    explanation: The original Sf9 recombinant assay shows that the C-terminal frameshift affects both activity groups. Historical GT terminology is retained only in the source quote.
pathophysiology:
- name: PLOD3 Biallelic Loss of Function
  description: Biallelic pathogenic variants can reduce LH3 abundance, stability and enzymatic activity. Human alleles need not selectively affect one catalytic function. The magnitude and combination of defects vary by allele and assay.
  biological_scale: MOLECULAR
  evidence:
  - reference: PMID:30089812
    reference_title: Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: LH3 N223S showed severely reduced lysyl hydroxylase and fully abolished glycosyltransferase activities
    explanation: Recombinant p.Asn223Ser impairs both activities; the study also found instability and degradation.
  - reference: PMID:30463024
    reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient.
    explanation: Patient tissue and cultured fibroblasts showed reduced LH3 protein.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: procollagen glucosyltransferase activity
    term:
      id: GO:0033823
      label: procollagen glucosyltransferase activity
    modifier: DECREASED
  - preferred_term: procollagen-lysine 5-dioxygenase activity
    term:
      id: GO:0008475
      label: procollagen-lysine 5-dioxygenase activity
    modifier: DECREASED
  downstream:
  - target: Reduced Collagen Hydroxylysine Glucosylation
    causal_link_type: DIRECT
    description: LH3 deficiency reduces glycosylated collagen hydroxylysine products.
    evidence:
    - reference: PMID:30463024
      reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine.
      explanation: The full manuscript identifies urine as the assayed material, not patient tissue. Total hydroxylysine relative to lysine was preserved in this patient.
  - target: Reduced Type IV Collagen Lysyl Hydroxylation
    causal_link_type: DIRECT
    description: Loss of LH3 decreases type IV collagen lysyl hydroxylation in knockout cells.
    evidence:
    - reference: PMID:36403858
      reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: more unmodified lysines (significantly fewer hydroxylysines), on COL4A1 and COL4A2 proteins isolated from LH3 KO PFHR9 cells
      explanation: Amino-acid analyses support reduced lysyl hydroxylation in type IV collagen in this knockout cell system.
- name: Reduced Collagen Hydroxylysine Glucosylation
  description: LH3 catalyzes addition of glucose to galactosyl-hydroxylysine. Direct mass-spectrometry assays assign the preceding galactose transfer to COLGALT1/GLT25D1. These enzymes form a 2:2 complex. Abnormal collagen glycosylation is supported by patient urinary products and by collagen analyses in knockout cells; it is not equivalent to loss of every sugar from every collagen. The process term includes elongation of a galactose-linked glycan; it does not assign the preceding galactose-transfer reaction to LH3.
  biological_scale: MOLECULAR
  evidence:
  - &id005
    reference: PMID:30463024
    reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine.
    explanation: The full manuscript identifies urine as the assayed material, not patient tissue. Total hydroxylysine relative to lysine was preserved in this patient.
  - reference: PMID:37446392
    reference_title: Identification of Regulatory Molecular "Hot Spots" for LH/PLOD Collagen Glycosyltransferase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: LH/PLOD enzymes are exclusively involved in the glucosylation of galactosyl hydroxylysines, whereas collagen galactosyltransferases, such as GLT25D1, are solely responsible for Hyl galactosylation.
    explanation: Direct product assays distinguish collagen glucosylation from galactosylation.
  - reference: PMID:40069201
    reference_title: The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex
    explanation: Cryo-EM and recombinant complex assays support coordinated modification by distinct enzymes.
  biological_processes:
  - preferred_term: Hydroxylysine-linked collagen glycosylation
    term:
      id: GO:0180062
      label: protein O-linked glycosylation via galactose
    modifier: DECREASED
  downstream:
  - target: Impaired Type VI Collagen Tetramerization
    causal_link_type: DIRECT
    description: Loss of glycosylated hydroxylysines impairs intracellular type VI tetramer assembly.
    evidence:
    - reference: PMID:17873278
      reference_title: Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens
      explanation: Knockout embryos and cultured cells link altered collagen glycosylation with defective type VI assembly and impaired secretion.
  - target: Abnormal Type IV Collagen Triple Helix
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced modification accompanies abnormal type IV triple-helix formation; the separate contribution of hydroxylation and glucosylation is unresolved.
    evidence:
    - reference: PMID:36403858
      reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: collagen α1α1α2(IV) produced by LH3 KO cells did not form stable triple helical helices
      explanation: Purified type IV collagen from knockout PFHR9 cells had abnormal circular-dichroism spectra and altered oligomerization.
  - target: Type VII Collagen Anchoring Fibril Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The PLOD3-deficient blistering patient had reduced type VII collagen and abnormal anchoring fibrils; direct biochemical proof of the intervening type VII modification defect is lacking.
    evidence:
    - reference: PMID:30463024
      reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced.
      explanation: Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.
  - target: Altered Extracellular Collagen Fibril Organization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced LH3-dependent modification accompanies abnormal extracellular fibrils in animal models; substrate-specific steps in humans remain unresolved.
    evidence:
    - reference: PMID:16467571
      reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung.
      explanation: Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      quote_role: PRIMARY_RESULT
      snippet: surrounded by sparse extracellular matrix lacking collagen fibrils
      explanation: Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.
- name: Reduced Type IV Collagen Lysyl Hydroxylation
  description: LH3 knockout reduces hydroxylysines in type IV collagen in PFHR9 cells. Type I and III collagen hydroxylation was largely preserved in the comparator fibroblast model. Selective LH-deficient mice survive but develop structural matrix abnormalities.
  biological_scale: MOLECULAR
  evidence:
  - &id011
    reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: more unmodified lysines (significantly fewer hydroxylysines), on COL4A1 and COL4A2 proteins isolated from LH3 KO PFHR9 cells
    explanation: Amino-acid analyses support reduced lysyl hydroxylation in type IV collagen in this knockout cell system.
  - &id002
    reference: PMID:16467571
    reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung.
    explanation: Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.
  biological_processes:
  - preferred_term: peptidyl-lysine hydroxylation
    term:
      id: GO:0017185
      label: peptidyl-lysine hydroxylation
    modifier: DECREASED
  downstream:
  - target: Abnormal Type IV Collagen Triple Helix
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Combined modification loss accompanies impaired helix formation; this experiment does not isolate the hydroxylation contribution.
    evidence:
    - reference: PMID:36403858
      reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: collagen α1α1α2(IV) produced by LH3 KO cells did not form stable triple helical helices
      explanation: Purified type IV collagen from knockout PFHR9 cells had abnormal circular-dichroism spectra and altered oligomerization.
- name: Impaired Type VI Collagen Tetramerization
  description: In LH3-null embryos and cultured cells, deficient hydroxylysine glycosylation impairs intracellular type VI collagen tetramerization. This model result is not a demonstrated uniform block in all patient tissues.
  biological_scale: MOLECULAR
  evidence:
  - &id001
    reference: PMID:17873278
    reference_title: Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens
    explanation: Knockout embryos and cultured cells link altered collagen glycosylation with defective type VI assembly and impaired secretion.
  downstream:
  - target: Impaired Type IV and VI Collagen Secretion
    causal_link_type: DIRECT
    description: Defective intracellular assembly is associated with impaired secretion of highly glycosylated collagens.
    evidence:
    - reference: PMID:17873278
      reference_title: Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens
      explanation: Knockout embryos and cultured cells link altered collagen glycosylation with defective type VI assembly and impaired secretion.
- name: Abnormal Type IV Collagen Triple Helix
  description: Type IV collagen isolated from LH3-knockout PFHR9 cells lacked a stable normal triple helix, showed altered HSP47 binding and failed to form normal higher-order assemblies. HSP47 binding was reduced or altered, rather than absent.
  biological_scale: MOLECULAR
  evidence:
  - &id012
    reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: collagen α1α1α2(IV) produced by LH3 KO cells did not form stable triple helical helices
    explanation: Purified type IV collagen from knockout PFHR9 cells had abnormal circular-dichroism spectra and altered oligomerization.
  downstream:
  - target: Impaired Type IV and VI Collagen Secretion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Abnormal collagen maturation accompanies delayed export in knockout cells.
    evidence:
    - reference: PMID:36403858
      reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture
      explanation: Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.
- name: Impaired Type IV and VI Collagen Secretion
  description: Secretion of type IV and VI collagen is impaired in LH3-deficient experimental systems. Type IV export remains detectable even in complete-knockout PFHR9 cells, and type I/III secretion was largely preserved in comparator fibroblasts. Human skin can retain normal type IV staining.
  biological_scale: CELLULAR
  evidence:
  - *id001
  - &id007
    reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture
    explanation: Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.
  - &id003
    reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the staining for type IV collagen appeared unaltered as compared to control
    explanation: 'Full accepted manuscript of PMID:30463024: preserved type IV immunostaining in this patient limits extrapolation of the complete-knockout secretion defect to every human tissue.'
  biological_processes:
  - preferred_term: protein secretion
    term:
      id: GO:0009306
      label: protein secretion
    modifier: DECREASED
  downstream:
  - target: Basement Membrane Disorganization
    causal_link_type: DIRECT
    description: Abnormal type IV localization compromises basement membrane assembly in the mouse model.
    evidence:
    - reference: PMID:16467571
      reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5
      explanation: Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.
  - target: Collagen Retention in the Endoplasmic Reticulum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced collagen handling is associated with intracellular retention; the patient-cell result concerns type I collagen.
    evidence:
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: COL1 (red) staining partially co-localized with ERp57 (ER marker; green)
      explanation: Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.
- name: Basement Membrane Disorganization
  description: LH3-deficient mice show abnormal basement membrane structure and type IV collagen distribution. The human blistering case had fragmented lamina densa but preserved type IV staining, indicating that matrix integrity cannot be inferred from staining abundance alone.
  biological_scale: TISSUE
  evidence:
  - &id008
    reference: PMID:16467571
    reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5
    explanation: Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.
  - *id002
  - *id003
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: while in some parts of skin the lamina densa appeared relatively intact, in other areas it was interrupted and fragmented
    explanation: Full accepted manuscript of PMID:30463024 documents structural basement-membrane abnormalities in patient skin.
  cellular_components:
  - preferred_term: basement membrane
    term:
      id: GO:0005604
      label: basement membrane
- name: Altered Extracellular Collagen Fibril Organization
  description: Selective hydroxylase-deficient mice show disorganized fibrils, and mutant zebrafish cartilage has sparse extracellular collagen fibrils. These findings support a matrix-organization defect, while the contribution of individual collagen substrates to human bone fragility remains unresolved.
  biological_scale: TISSUE
  evidence:
  - *id002
  - &id009
    reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: surrounded by sparse extracellular matrix lacking collagen fibrils
    explanation: Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: ABNORMAL
- name: Type VII Collagen Anchoring Fibril Disruption
  description: The p.Leu627Pro patient had reduced type VII collagen, variable anchoring-fibril density and morphology, and sub-lamina-densa cleavage. Some areas retained normal-looking fibrils. Negative testing across epidermolysis-bullosa genes and PLOD3 functional findings support this association without making negative COL7A1 testing alone proof of causality.
  biological_scale: TISSUE
  evidence:
  - &id004
    reference: PMID:30463024
    reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced.
    explanation: Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.
  downstream:
  - target: Abnormal blistering of the skin
    causal_link_type: DIRECT
    description: The abnormal anchoring-fibril system is associated with separation below the lamina densa.
    evidence:
    - reference: PMID:30463024
      reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced.
      explanation: Patient skin directly demonstrated a disrupted anchoring-fibril system and sub-lamina-densa cleavage. The study did not directly measure type VII collagen glycosylation.
- name: Collagen Retention in the Endoplasmic Reticulum
  description: Patient-derived fibroblasts carrying the splice-altering c.1354C>T allele show collagen I colocalization with ER markers and distended ER. Mutant zebrafish chondrocytes accumulate collagen II intracellularly, although extracellular collagen II remains detectable.
  biological_scale: CELLULAR
  evidence:
  - &id013
    reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: COL1 (red) staining partially co-localized with ERp57 (ER marker; green)
    explanation: Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: PERK Branch Unfolded Protein Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Collagen retention and ER distension accompany PERK-branch activation; the sequence is supported by paired model readouts rather than a selective retention intervention.
    evidence:
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish
      explanation: The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.
- name: PERK Branch Unfolded Protein Response
  description: Mutant zebrafish and patient fibroblast studies show ER stress with increased PERK-branch readouts. The data do not establish this response as the cause of organ damage; inhibitor experiments did not rescue the zebrafish phenotype and the authors proposed an adaptive role.
  biological_scale: CELLULAR
  evidence:
  - &id010
    reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish
    explanation: The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Comparative TEM and immunoblot analyses in the patient’s fibroblasts confirmed these findings
    explanation: The patient-cell comparison also showed distended ER and corresponding stress-response protein changes.
  biological_processes:
  - preferred_term: PERK-mediated unfolded protein response
    term:
      id: GO:0036499
      label: PERK-mediated unfolded protein response
    modifier: INCREASED
phenotypes:
- category: Skeletal
  name: Reduced bone mineral density
  description: Low bone mineral density with bone fragility, one of the naming features of the syndrome.
  phenotype_term:
    preferred_term: Reduced bone mineral density
    term:
      id: HP:0004349
      label: Reduced bone mineral density
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection."
    explanation: The collated feature list from the review that proposed the diagnostic label.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Skeletal
  name: Joint contracture
  description: Finger and joint contractures, another naming feature.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "finger contractures, prominent knees, scoliosis"
    explanation: Names the contractures among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Skeletal
  name: Scoliosis
  description: Reported among the collated skeletal features.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prominent knees, scoliosis, low bone mineral density"
    explanation: Names scoliosis among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Ophthalmologic
  name: Cataract
  description: Cataract can be congenital or appear during childhood; it is absent in some reported patients.
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized by bone abnormalities, cataract, risk of arterial rupture due to vascular aneurisms or dissections, and sensorineural deafness"
    explanation: The syndrome definition, which names cataract as a cardinal feature.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Ophthalmologic
  name: Retinal detachment
  description: >-
    Retinal detachment risk, part of the Stickler-like ocular picture and one of the reasons
    early recognition matters.
  phenotype_term:
    preferred_term: Retinal detachment
    term:
      id: HP:0000541
      label: Retinal detachment
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular abnormalities with risk for retinal detachment"
    explanation: Names the retinal detachment risk directly.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Auditory
  name: Sensorineural hearing impairment
  description: Sensorineural deafness, the D of BCARD.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss, reduced palmar creases, finger contractures"
    explanation: Names sensorineural hearing loss among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Cardiovascular
  name: Arterial dissection
  description: >-
    Arterial dissection and rupture risk are reported. Large-vessel complications are variable and may develop
    after early childhood.
  phenotype_term:
    preferred_term: Arterial dissection
    term:
      id: HP:0005294
      label: Arterial dissection
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "risk of arterial rupture due to vascular aneurisms or dissections"
    explanation: >-
      The vascular feature as stated in the syndrome definition. Quoted including the
      source's spelling "aneurisms", since a snippet reproduces its source.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Neurologic
  name: Global developmental delay
  description: Developmental delay is variable. In the founding patient, walking began at four years and communication used sign language; profound sensory impairments and joint contractures complicate attribution to intrinsic cognitive dysfunction.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "craniofacial dysmorphisms, developmental delay and risk for vascular dissection"
    explanation: Names developmental delay among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Development was globally delayed. She walked independently at 4 years of age.
    explanation: Direct clinical documentation of global delay in the founding patient.
- category: Ophthalmologic
  name: High myopia
  description: Severe myopia was explicitly reported in the p.Leu627Pro child. Other patients had less severe refractive errors; high myopia is not inferred from the general Stickler-like resemblance.
  phenotype_term:
    preferred_term: High myopia
    term:
      id: HP:0011003
      label: High myopia
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The patient was born with a right eye cataract, ptosis, severe myopia
    explanation: Full accepted manuscript of PMID:30463024 explicitly identifies severe myopia.
- category: Craniofacial
  name: Abnormal facial shape
  description: Recognisable craniofacial dysmorphism, reported among the collated features.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection"
    explanation: Names the craniofacial dysmorphism among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Dermatologic
  name: Abnormal palmar crease morphology
  description: Reduced palmar creases, reported among the collated features.
  phenotype_term:
    preferred_term: reduced palmar creases
    term:
      id: HP:0010490
      label: Abnormal palmar crease morphology
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sensorineural hearing loss, reduced palmar creases, finger contractures"
    explanation: Names the reduced palmar creases among the collated key features.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Renal
  name: Vesicoureteral reflux
  description: >-
    Vesicoureteral reflux was reported in the 2025 patient. Frequency and the full genotype-phenotype relationship
    remain uncertain.
  phenotype_term:
    preferred_term: Vesicoureteral reflux
    term:
      id: HP:0000076
      label: Vesicoureteral reflux
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: Reports vesico-ureteral reflux in the patient whose case expanded the phenotype.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Gastrointestinal
  name: Abnormal intestine morphology
  description: An unspecified intestinal anomaly was reported in the 2025 patient. Frequency and the full genotype-phenotype relationship remain uncertain.
  phenotype_term:
    preferred_term: Abnormal intestine morphology
    term:
      id: HP:0002242
      label: Abnormal intestine morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: >-
      Reports an intestinal anomaly. Bound to the generic intestinal-morphology term because
      the source names no specific lesion.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Cardiovascular
  name: Abnormal heart morphology
  description: Unspecified minor cardiac anomalies were reported in the 2025 patient. Frequency and the full genotype-phenotype relationship remain uncertain.
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
    coarse_binding_basis: SOURCE_UNSPECIFIED
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: >-
      Reports minor cardiac anomalies. Bound to the generic heart-morphology term because the
      source characterises them as minor without naming a lesion.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Neurologic
  name: Focal-onset seizure
  description: Focal epilepsy was reported in the 2025 patient. Frequency and the full genotype-phenotype relationship remain uncertain.
  phenotype_term:
    preferred_term: Focal-onset seizure
    term:
      id: HP:0007359
      label: Focal-onset seizure
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: Reports focal epilepsy in the patient whose case expanded the phenotype.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Neurologic
  name: Polymicrogyria
  description: >-
    Polymicrogyria was reported in the 2025 patient. Frequency and the full genotype-phenotype relationship
    remain uncertain.
  phenotype_term:
    preferred_term: Polymicrogyria
    term:
      id: HP:0002126
      label: Polymicrogyria
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: Reports polymicrogyria among the brain abnormalities in the expanded phenotype.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Neurologic
  name: Gray matter heterotopia
  description: Gray matter heterotopia of unspecified distribution was reported in the 2025 patient. Frequency and the full genotype-phenotype relationship remain uncertain.
  phenotype_term:
    preferred_term: Gray matter heterotopia
    term:
      id: HP:0002282
      label: Gray matter heterotopia
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia"
    explanation: >-
      Reports heterotopia. Bound to the generic gray-matter-heterotopia term because the
      source does not specify its distribution.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
- category: Dermatologic
  name: Abnormal blistering of the skin
  description: >-
    Blistering was reported in the founding patient and in the p.Leu627Pro child. The latter had sub-lamina-densa
    separation, reduced type VII collagen and abnormal anchoring fibrils. Other patients have no blistering;
    a 2022 review recorded it in two of nine previously reported individuals.
  phenotype_term:
    preferred_term: Abnormal blistering of the skin
    term:
      id: HP:0008066
      label: Abnormal blistering of the skin
  evidence:
  - *id004
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Blistering affecting all toes and fingers and blistering of the pinnae was present
    explanation: The founding patient also had skin blistering, which healed without scarring.
- name: Recurrent fractures
  category: Skeletal
  description: Multiple healed fractures accompanied osteopenia in the founding patient.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Osteopenia and healed fractures of the left clavicle, right femur, and right humerus were seen.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Talipes equinovarus
  category: Skeletal
  description: Congenital clubfoot has been reported, including surgically corrected bilateral deformity.
  phenotype_term:
    preferred_term: Talipes equinovarus
    term:
      id: HP:0001762
      label: Talipes equinovarus
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Skeletal problems included bilateral talipes equinovarus requiring surgical correction
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Platyspondyly
  category: Skeletal
  description: Flattened vertebrae were described in the founding and 2022 patients.
  phenotype_term:
    preferred_term: Platyspondyly
    term:
      id: HP:0000926
      label: Platyspondyly
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The vertebrae were flattened, and the lower and upper edges were slightly concave.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Diaphragmatic eventration
  category: Respiratory
  description: Right-sided eventration required repeat repair in the founding patient; the p.Leu627Pro child had spontaneous improvement.
  phenotype_term:
    preferred_term: Diaphragmatic eventration
    term:
      id: HP:0009110
      label: Diaphragmatic eventration
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A right-sided diaphragmatic eventration was repaired when the patient was 5 months of age.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Intrauterine growth retardation
  category: Growth
  description: Marked prenatal growth restriction occurred in the founding patient, but was absent in the p.Leu627Pro child.
  phenotype_term:
    preferred_term: Intrauterine growth retardation
    term:
      id: HP:0001511
      label: Intrauterine growth retardation
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Pregnancy was complicated by intrauterine growth retardation (IUGR).
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Short stature
  category: Growth
  description: Postnatal growth restriction is reported in several cases; the founding patient remained below two standard deviations.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Postnatally, growth continued below −2 standard deviations.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Thin skin
  category: Dermatologic
  description: Thin poorly perfused skin was observed in the founding patient.
  phenotype_term:
    preferred_term: Thin skin
    term:
      id: HP:0000963
      label: Thin skin
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The skin appeared to be thin and poorly perfused but with no significant abnormalities of healing or scarring.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Easy bruising
  category: Dermatologic
  description: Bruising occurred despite normal routine coagulation tests and platelet count in the founding patient.
  phenotype_term:
    preferred_term: Easy bruising
    term:
      id: HP:0000978
      label: Bruising susceptibility
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Bruising occurred readily but prothrombin and partial thromboplastin times and platelet counts were all found to be normal.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Nail hypoplasia
  category: Dermatologic
  description: Hypoplastic nails with progressive atrophy were described in the founding patient.
  phenotype_term:
    preferred_term: Nail hypoplasia
    term:
      id: HP:0001792
      label: Small nail
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: All nails were hypoplastic, although the small, dysplastic fingernails were described as “rapidly-growing with brittle tips”
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Cerebral hemorrhage
  category: Neurologic
  description: The founding patient developed a spontaneous cerebral arterial hemorrhage at eleven years; a later infant had multiple bleeding foci on imaging.
  phenotype_term:
    preferred_term: Cerebral hemorrhage
    term:
      id: HP:0001342
      label: Cerebral hemorrhage
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: a spontaneous cerebral arterial haemorrhage presented with hemiplegia.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Infantile spasms
  category: Neurologic
  description: Clustered spasms began at eight months in the homozygous p.Leu406del child; this is a single reported presentation.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: At 8 months of age, she presented with clustered epileptic spasms.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Hypsarrhythmia
  category: Neurologic
  description: Hypsarrhythmia supported the diagnosis of West syndrome in the 2022 child.
  phenotype_term:
    preferred_term: Hypsarrhythmia
    term:
      id: HP:0002521
      label: Hypsarrhythmia
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The imaging features of the patient were consistent with the diagnosis of cerebral SVD. Electroencephalography (EEG) suggested hypsarrhythmia.
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Ptosis
  category: Ophthalmologic
  description: Congenital unilateral ptosis was surgically corrected in the p.Leu627Pro child.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Ophthalmologic surgery to correct unilateral ptosis was performed at 10 months of age.
    explanation: Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.
- name: Strabismus
  category: Ophthalmologic
  description: Strabismus accompanied other ocular abnormalities in the p.Leu627Pro child.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Ophthalmologic examination showed amblyopia and strabismus, in addition to his neonatal ophthalmologic findings
    explanation: Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.
- name: Amblyopia
  category: Ophthalmologic
  description: Amblyopia was documented in the p.Leu627Pro child.
  phenotype_term:
    preferred_term: Amblyopia
    term:
      id: HP:0000646
      label: Amblyopia
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Ophthalmologic examination showed amblyopia and strabismus, in addition to his neonatal ophthalmologic findings
    explanation: Full accepted manuscript of PMID:30463024. Reported human clinical finding; no disease-wide frequency is inferred.
- name: Microcephaly
  category: Neurologic
  description: Microcephaly is part of the clinical description associated with c.1354C>T; the role of specific collagen substrates in this phenotype remains uncertain.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Midface retrusion
  category: Craniofacial
  description: Midfacial hypoplasia was reported in individuals carrying c.1354C>T.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Micrognathia
  category: Craniofacial
  description: Micrognathia was reported in individuals carrying c.1354C>T.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: BACKGROUND
    snippet: developmental delay, microcephaly, midfacial hypoplasia, depressed nasal bridge, micrognathia, truncal hypotonia, and distal arthrogryposis
    explanation: Reported human clinical finding; no disease-wide frequency is inferred.
- name: Popliteal Artery Aneurysm
  category: Cardiovascular
  description: The founding patient developed a ruptured right popliteal aneurysm during the second decade. The vascular-dilatation binding is broader than this documented peripheral arterial lesion.
  phenotype_term:
    preferred_term: Popliteal Artery Aneurysm
    term:
      id: HP:0002617
      label: Vascular dilatation
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A spontaneous rupture of a right popliteal aneurysm ... presented with pain and swelling.
    explanation: Direct clinical documentation of a ruptured peripheral arterial aneurysm.
- name: Carotid Artery Dilatation
  category: Cardiovascular
  description: At age fourteen, the founding patient had gross dilatation of both internal carotid arteries on CT.
  phenotype_term:
    preferred_term: Carotid Artery Dilatation
    term:
      id: HP:0012163
      label: Carotid artery dilatation
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: A subsequent CT scan when the patient was 14 years of age demonstrated gross dilatation of both internal carotids
    explanation: The documented carotid lesion is recorded separately from the ruptured popliteal aneurysm.
- name: Multiple pterygia
  category: Musculoskeletal
  description: The p.Leu627Pro child had pterygia at multiple joints and initially carried an Escobar syndrome diagnosis.
  phenotype_term:
    preferred_term: Multiple pterygia
    term:
      id: HP:0001040
      label: Multiple pterygia
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: He had pterygia of the neck, axilla, antecubital, popliteal, digital and intercrural areas.
    explanation: Full accepted manuscript of PMID:30463024 documents the distribution.
- name: Poor wound healing
  category: Dermatologic
  description: Delayed healing accompanied trauma-induced blistering in the p.Leu627Pro child. The founding patient had no significant healing abnormality, illustrating variable skin involvement.
  phenotype_term:
    preferred_term: Poor wound healing
    term:
      id: HP:0001058
      label: Poor wound healing
  evidence:
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: trauma-induced skin blisters over the prominent body areas, particularly on elbows, feet, knees, and ears with history of delayed wound healing
    explanation: Full accepted manuscript of PMID:30463024 reports delayed wound healing.
- name: Low-set ears
  category: Craniofacial
  description: Low-set ears are described in the founding, blistering and 2022 neurologic cases.
  phenotype_term:
    preferred_term: Low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Dysmorphic features included hypertelorism, an upturned nose, and low‐set ears
    explanation: The neurologic case provides a specific facial finding rather than only a coarse dysmorphism label.
biochemical:
- name: Reduced urinary glycosylated hydroxylysine
  presence: PRESENT
  notes: In the p.Leu627Pro child, urinary glycosylated hydroxylysine relative to hydroxylysine was markedly reduced, while total hydroxylysine relative to lysine and the disaccharide/monosaccharide ratio were preserved. The founding patient had absent urinary glucosyl-galactosyl pyridinoline and an altered hydroxylysine glycoside ratio. These assays support collagen-modification dysfunction; sensitivity, specificity and diagnostic cutoffs for BCARD have not been established.
  evidence:
  - &id006
    reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the ratio of (GGHL + GHL)/HL in the proband was reduced to about 17% of that measured in his parents
    explanation: 'Full accepted manuscript of PMID:30463024: urinary glycosylated hydroxylysine relative to hydroxylysine was about 17% of parental values. This is a single-family functional observation, not a validated diagnostic cutoff.'
  - *id005
  readouts:
  - target: Reduced Collagen Hydroxylysine Glucosylation
    relationship: READOUT_OF
    direction: NEGATIVE
    interpretation: Reduced glycosylated hydroxylysine products reflect defective collagen modification, but do not isolate every enzyme step or establish diagnostic specificity.
    evidence:
    - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
      reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the ratio of (GGHL + GHL)/HL in the proband was reduced to about 17% of that measured in his parents
      explanation: 'Full accepted manuscript of PMID:30463024: urinary glycosylated hydroxylysine relative to hydroxylysine was about 17% of parental values. This is a single-family functional observation, not a validated diagnostic cutoff.'
prevalence:
- population: Worldwide, reported cases
  measure_type: CASES_IN_LITERATURE
  notes: >-
    The 2025 report described ten previously published cases across six reports and added an 11-year-old girl.
    This is a dated literature count, not a population prevalence or a current total.
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was characterized in 10 cases across six reports"
    explanation: The published case count, which is the only occurrence figure available.
    directness: DIRECT
    quote_role: PRIMARY_RESULT
treatments:
- name: Vascular Surveillance
  description: >-
    Monitor for arterial aneurysm and dissection in a specialist setting. The case-series authors recommend
    early recognition and monitoring; no comparative outcome study or validated surveillance interval establishes
    its benefit in BCARD.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes."
    explanation: >-
      The authors recommend monitoring to reduce ocular and vascular morbidity; this is a proposed benefit,
      not a measured treatment effect.
    quote_role: PRIMARY_RESULT
- name: Ophthalmologic Surveillance
  description: >-
    Ophthalmologic follow-up addresses cataract, refractive error and retinal detachment risk. Recommendations
    arise from the clinical spectrum and expert interpretation of small case series.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:31129566
    reference_title: Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early identification of PLOD3 variants would improve monitoring for comorbidities and may avoid serious adverse ocular and vascular outcomes."
    explanation: >-
      The authors recommend monitoring to reduce ocular and vascular morbidity; this is a proposed benefit,
      not a measured treatment effect.
    quote_role: PRIMARY_RESULT
- name: Cochlear Implantation
  description: Profound bilateral sensorineural deafness was treated with cochlear implantation in the founding patient. The report does not quantify hearing improvement.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: cochlear implant
        term:
          id: NCIT:C157820
          label: Cochlear Implant
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: was treated with cochlear implantation.
    explanation: The original case reports an actual audiologic intervention, without a quantified postoperative outcome.
  therapeutic_modality: DEVICE
- name: Orthopedic Surgery
  description: Bilateral clubfoot required surgical correction in the founding patient. Treatment of skeletal abnormalities is individualized; this report does not establish a bone-directed drug regimen.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Skeletal problems included bilateral talipes equinovarus requiring surgical correction
    explanation: Directly documented orthopedic intervention.
  therapeutic_modality: SURGERY
- name: Ocular Surgery
  description: Cataracts required surgery at seven years in the founding patient, and unilateral ptosis was corrected at ten months in the p.Leu627Pro child. These are reported interventions, not comparative efficacy estimates.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: cataracts requiring surgery at age 7 of the patient
    explanation: Cataract surgery was documented in the original case.
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Ophthalmologic surgery to correct unilateral ptosis was performed at 10 months of age.
    explanation: Full accepted manuscript of PMID:30463024 documents ptosis correction.
  therapeutic_modality: SURGERY
- name: Repair of Symptomatic Diaphragmatic Eventration
  description: The founding patient required two repairs after the initial repair failed in a friable diaphragm. The p.Leu627Pro child improved without intervention, so surgery is not uniformly required.
  treatment_term:
    preferred_term: Surgical Procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The diaphragm was noted to be friable; the initial repair failed and a second surgical repair was needed.
    explanation: The report describes operative failure followed by repeat repair.
  - reference: url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    reference_title: https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Diaphragmatic eventration disappeared with aging without intervention.
    explanation: Full accepted manuscript of PMID:30463024 documents spontaneous improvement in a different child.
  therapeutic_modality: SURGERY
- name: Treatment of Infantile Spasms
  description: In the p.Leu406del child, two weeks of ACTH did not reduce spasms. Subsequent topiramate, valproate, nitrazepam and vigabatrin reduced frequency by no more than half, with persistent spasms at fourteen months. A ketogenic diet was suggested but no response was reported. These observations describe one refractory case.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticotropin
      term:
        id: CHEBI:3892
        label: corticotropin
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: sodium valproate
      term:
        id: CHEBI:9925
        label: sodium valproate
    - preferred_term: nitrazepam
      term:
        id: CHEBI:7581
        label: nitrazepam
    - preferred_term: vigabatrin
      term:
        id: CHEBI:63638
        label: vigabatrin
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: but seizure frequency did not change. Multiple antiepileptic drugs (AEDs) were added
    explanation: The child did not respond to the reported ACTH course; additional drugs were then introduced.
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The seizure frequency was reduced by no more than 50%.
    explanation: Incomplete response after multidrug treatment in a single case.
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Adrenocorticotrophic hormone ... was administered for two consecutive weeks ... Multiple antiepileptic drugs (AEDs) were added, including topiramate ... sodium valproate ... nitrazepam ... and vigabatrin
    explanation: The report identifies ACTH followed by these four antiseizure drugs; it does not isolate a response to each agent.
  therapeutic_modality: OTHER
- name: Genetic Counseling and Family Testing
  description: Discuss autosomal recessive inheritance and test relatives for the familial alleles. When both parents are heterozygous carriers, Mendelian recurrence is one in four per pregnancy. RNA or functional studies may be needed to interpret splice-altering or otherwise uncertain variants.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: Our restriction analysis indicated that mutation 1 was inherited from the father and mutation 2 was inherited from the mother
    explanation: Parental segregation supports recessive counseling; the recurrence fraction follows Mendelian inheritance, not an observed cohort rate.
diagnosis:
- name: Biallelic PLOD3 Molecular Diagnosis
  description: Sequence PLOD3 in a patient with compatible connective tissue features, using a panel or exome/genome approach as appropriate, and establish segregation of candidate alleles. A rare variant or computational prediction alone does not confirm BCARD.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30463024
    reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3).
    explanation: Documents the molecular route in the blistering patient.
- name: RNA Analysis of Suspected Splice-Altering Variants
  description: Transcript analysis can establish an unexpected splice consequence, including an in-frame deletion instead of a predicted stop-gain product. Results need interpretation in the assayed tissue and alongside phenotype and segregation.
  evidence:
  - reference: PMID:40289369
    reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The first variant functions as a cryptic splice site variant, and RNA analysis confirmed that it causes a 4 bp truncation of exon 3.
    explanation: The reported c.335A>G allele acts through aberrant splicing; the resulting frameshift is p.Asp112AlafsTer4.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the c.1354 C > T transition created a premature GT splice donor site leading to a 6-bp in frame deletion
    explanation: Patient-derived RNA showed an in-frame deletion affecting Arg452 and Val453; a predicted stop-gain annotation does not describe the observed transcript.
- name: Collagen Modification and LH3 Protein Studies
  description: Urinary collagen-derived hydroxylysine glycosides and pyridinoline products, or LH3 protein measurements in patient-derived cells, can support a functional defect. Availability is limited and validated BCARD diagnostic thresholds are not established. Reduced glycosylation products can also occur in ARC syndrome.
  evidence:
  - *id006
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Western blotting showed markedly reduced levels of LH3 in the patient
    explanation: Patient fibroblasts showed reduced LH3; urine pyridinoline and enzyme activity were not measured in this case.
- name: Skin Ultrastructure in Blistering Presentations
  description: Sub-lamina-densa cleavage, abnormal anchoring fibrils and reduced type VII collagen can resemble COL7A1-related dystrophic epidermolysis bullosa. Molecular testing and the multisystem presentation determine the diagnosis; immunostaining alone is not PLOD3-specific.
  evidence:
  - *id004
- name: Neuroimaging and EEG for Neurologic Presentations
  description: MRI and EEG characterized bleeding foci, white-matter abnormalities, cerebral atrophy and hypsarrhythmia in the p.Leu406del child. Normal MRA/MRV did not exclude the imaging-based small-vessel phenotype. This is diagnostic characterization of a symptomatic case, not a universal screening protocol.
  evidence:
  - reference: PMID:36203519
    reference_title: 'Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The imaging features of the patient were consistent with the diagnosis of cerebral SVD. Electroencephalography (EEG) suggested hypsarrhythmia.
    explanation: MRI supported small-vessel involvement and EEG identified the epileptic pattern; no vascular biopsy established the mechanism.
external_assertions:
- name: OMIM bone fragility with contractures, arterial rupture, and deafness record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:612394
  url: https://omim.org/entry/612394
  description: >-
    OMIM phenotype record for the PLOD3-related recessive connective tissue disorder.
classifications:
  mechanistic_category:
  - classification_value: collagenopathy
    evidence:
    - reference: PMID:17873278
      reference_title: Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results provide new information about the function of hydroxylysine-linked carbohydrates of collagens, indicating that they play an important role in the secretion, assembly, and distribution of highly glycosylated collagen types."
      explanation: >-
        Places the lesion in collagen post-translational modification, secretion and
        assembly, which is what makes this a collagenopathy rather than a generic
        extracellular matrix disorder.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:40289369
      reference_title: Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "BCARD syndrome is a rare autosomal recessive connective tissue disorder"
      explanation: >-
        Places the disorder among the heritable disorders of connective tissue, which
        Harrison's covers in its immunology and rheumatology part.
      directness: DIRECT
      quote_role: PRIMARY_RESULT
discussions:
- discussion_id: plod3_collagen_specificity
  kind: HUMAN_MODEL_MISMATCH
  prompt: How do collagen substrate, tissue and residual LH3 activity determine the human phenotype?
  attaches_to:
  - pathophysiology#Impaired Type IV and VI Collagen Secretion
  rationale: Complete knockout markedly impairs type IV secretion in PFHR9 cells, while comparator fibroblasts retain type I/III secretion and a patient skin biopsy retains type IV immunostaining. These different readouts and systems do not support universal collagen secretion failure. Specific causal routes to hearing loss, retinal disease, bone fragility, cortical malformations and visceral anomalies remain incompletely resolved; organ expression alone does not establish those routes.
  evidence:
  - *id007
  - *id003
  - reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the secretion rates of fibrillar collagens α1α1α2(I) and α1α1α1(III) were comparable between WT and LH3 KO MEFs
    explanation: The fibroblast comparison demonstrates collagen- and model-dependent secretion effects.
- discussion_id: plod3_complex_and_variant_effects
  kind: OPEN_QUESTION
  prompt: Which patient alleles disrupt LH3-COLGALT1 assembly rather than catalytic activity or protein stability?
  attaches_to:
  - pathophysiology#PLOD3 Biallelic Loss of Function
  rationale: Direct assays and structures support distinct LH3 glucosyltransferase and COLGALT1 galactosyltransferase functions. Remaining uncertainty concerns allele-specific coupling and the physiological role of higher-order enzyme assemblies. Recombinant p.Pro270Leu could not be assayed reliably because protein yield was extremely low. Engineered substitutions at the LH3 interface, including Arg452, do not by themselves prove the mechanism of the patient Arg452_Val453 deletion.
  evidence:
  - reference: PMID:37446392
    reference_title: Identification of Regulatory Molecular "Hot Spots" for LH/PLOD Collagen Glycosyltransferase Activity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: due to the almost non-detectable protein levels, we could not reliably carry out any in vitro investigations.
    explanation: Recombinant p.Pro270Leu production was too low for reliable activity assays; this supports a stability concern but does not demonstrate selective loss of glucosyltransferase activity.
  - reference: PMID:40069201
    reference_title: The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The biological significance of KOGG’s linear polymerization remains unclear
    explanation: The structural study explicitly leaves the physiological higher-order assembly unresolved.
- discussion_id: plod3_trafficking_versus_enzymatic_loss
  kind: OPEN_QUESTION
  prompt: How much of BCARD reflects the post-Golgi pool of LH3?
  attaches_to:
  - pathophysiology#PLOD3 Biallelic Loss of Function
  rationale: VIPAR/VPS33B and sequential RAB10/RAB25 activity deliver LH3 to collagen-IV-containing carriers. ARC models and patients demonstrate collagen-modification abnormalities after trafficking defects, but ARC is not PLOD3-related BCARD. The relative contribution of ER and post-Golgi LH3 to BCARD has not been isolated by these studies.
  evidence:
  - reference: PMID:27435297
    reference_title: Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: the N terminus of VIPAR as a novel indirect interactor of LH3
    explanation: The interaction is indirect; an intervening transmembrane partner was unresolved.
  - reference: PMID:27435297
    reference_title: Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
    snippet: testing urine available from three different ARC patients with known mutations in VPS33B showed a substantial decrease in all LH3-dependent post-translational lysine modifications
    explanation: Reduced urinary collagen-modification products are not specific to PLOD3 deficiency.
- discussion_id: plod3_succinate_translation
  kind: KNOWLEDGE_GAP
  prompt: Can the developmental zebrafish succinate response translate into treatment of human BCARD?
  attaches_to:
  - animal_models#mgtm635 plod3 Zebrafish
  rationale: Early larval exposure improved body length and muscle geometry and shifted selected transcripts toward control levels. It did not establish human efficacy, safety, a measured succinate or ATP deficiency, post-onset rescue, or correction of established vascular and auditory complications. Increased autophagy markers may reflect adaptation or impaired turnover; inhibitor nonresponse does not resolve causality.
  evidence:
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: SA treatment significantly reduced the somite angle in treated animals by approximately 12%, trending towards WT levels
    explanation: The reported benefit is a developmental zebrafish endpoint.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Expression analysis of SA-treated animals by qPCR found no significant changes in transcript levels of plod3, and the UPR genes bip and ddit3
    explanation: The experiment did not demonstrate significant reversal of these UPR transcript readouts.
- discussion_id: plod3_fetal_hemorrhage_variants
  kind: KNOWLEDGE_GAP
  prompt: Are the candidate PLOD3 variants in isolated fetal intracranial hemorrhage causal?
  attaches_to:
  - genetic#PLOD3
  rationale: A 113-fetus study found no enrichment of rare predicted damaging PLOD3 variants. One fetus carried p.Leu198Pro alone and another carried p.Arg197Trp/p.Pro489Leu in trans; all three were ACMG class 3 in that report and had no patient functional validation. These findings do not establish dominant PLOD3 disease or count as confirmed BCARD cases.
  evidence:
  - reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: We did not find an enrichment of rare and predicted damaging PLOD3 qualifying variants between this cohort and the gnomAD control database
    explanation: The study had a negative burden comparison.
  - reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Additional in vitro experiments are required to determine the causality of these variants
    explanation: The authors explicitly leave causality unresolved.
differential_diagnoses:
- name: Stickler Syndrome
  description: Ocular, auditory and skeletal features overlap.
  distinguishing_features:
  - PLOD3-related disease can add arterial rupture, skin blistering, nail abnormalities and prenatal growth restriction; molecular testing resolves the overlap.
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: By contrast, growth retardation, nail and skin abnormalities, osteopenia, joint contractures, and spontaneous vascular rupture are not seen in Stickler syndrome.
    explanation: The founding report discusses features differentiating that patient from the then-recognized Stickler spectrum; the comparison is source-specific.
- name: COL7A1-Related Dystrophic Epidermolysis Bullosa
  description: Sub-lamina-densa blistering and abnormal type VII collagen anchoring fibrils can closely resemble the PLOD3 blistering presentation.
  distinguishing_features:
  - PLOD3 disease includes skeletal, ocular and other multisystem findings; biallelic pathogenic PLOD3 variants and functional studies support its diagnosis. Negative COL7A1 testing alone does not prove the alternative.
  evidence:
  - reference: PMID:30463024
    reference_title: Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: No mutations in COL7A1, the gene previously associated with RDEB, were detected.
    explanation: The patient underwent epidermolysis-bullosa gene testing before the PLOD3 diagnosis.
  - *id004
- name: COL4A1/COL4A2-Related Gould Syndrome
  description: Cerebral hemorrhage, ocular abnormalities and small-vessel disease can overlap.
  distinguishing_features:
  - Established BCARD is recessive and often includes contractures, skeletal fragility and hearing impairment. Candidate PLOD3 variants in otherwise isolated fetal hemorrhage require separate pathogenicity assessment.
  evidence:
  - reference: PMID:36403858
    reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Additional in vitro experiments are required to determine the causality of these variants
    explanation: The fetal hemorrhage study did not establish its candidate PLOD3 variants as causal.
- name: Arthrogryposis-Renal Dysfunction-Cholestasis Syndrome
  description: VPS33B/VIPAS39 defects impair LH3 trafficking and can reduce collagen glycosylation products, creating biochemical and connective tissue overlap.
  distinguishing_features:
  - Renal dysfunction, cholestasis and platelet alpha-granule defects point toward ARC; PLOD3-related BCARD has a different molecular cause.
  evidence:
  - reference: PMID:27435297
    reference_title: Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: ARC syndrome caused by VPS33B or VIPAR deficiencies results in abnormal kidney and liver function, extremely dry skin (ichthyosis), defective platelet α-granule biogenesis, osteopaenia and recurrent bone fractures
    explanation: The trafficking study defines the clinically distinct ARC context.
- name: PLOD1-Related Kyphoscoliotic Ehlers-Danlos Syndrome
  description: Arterial fragility and osteopenia overlap with BCARD.
  distinguishing_features:
  - The founding BCARD case lacked the characteristic joint laxity, congenital scoliosis and scleral fragility considered for PLOD1-related disease; molecular and biochemical testing distinguish the disorders.
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Arterial rupture and osteopenia are both features of EDS VI ... whereas other major features of this disease, namely joint laxity, congenital scoliosis, scleral fragility, and the characteristic facial appearance, were absent in this patient.
    explanation: The founding report gives a patient-specific comparison to PLOD1-related EDS VI.
- name: Bruck Syndrome
  description: Bone fragility with contractures overlaps with PLOD3 disease.
  distinguishing_features:
  - The broader ocular, auditory, skin and vascular phenotype can suggest BCARD; PLOD2-related Bruck syndrome affects a different collagen-modifying enzyme.
  evidence:
  - reference: PMID:18834968
    reference_title: A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: Although osteopenia is a feature of EDS VI, caused by PLOD1 mutations, associated fractures are more in keeping with Bruck syndrome ... caused by PLOD2 mutations
    explanation: The founding report discusses Bruck syndrome in the differential.
animal_models:
- name: LH3 Activity-Selective and Hypomorphic Mice
  species: Mus musculus
  description: A hydroxylase-selective mutant develops but has basement-membrane and fibril defects. Reduced glucosyltransferase activity in a hypomorphic line causes embryonic lethality at E9.5–14.5; survival tracks residual activity. These manipulations do not reproduce the mixed effects of every human allele.
  publication: PMID:16467571
  evidence:
  - *id002
  - *id008
  modeled_mechanisms:
  - target: Basement Membrane Disorganization
    relationship: PARTIALLY_RECAPITULATES
    limitations: Embryonic mouse matrix failure differs from the variable, survivable human syndrome.
    evidence:
    - reference: PMID:16467571
      reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the reduction of the GGT activity of LH3 disrupts the localization of type IV collagen, and thus the formation of basement membranes during mouse embryogenesis leading to lethality at embryonic day (E) 9.5-14.5
      explanation: Hypomorphic mice connect residual glucosyltransferase activity to collagen IV localization, basement membrane formation and embryonic survival.
  - target: Altered Extracellular Collagen Fibril Organization
    relationship: PARTIALLY_RECAPITULATES
    limitations: Selective hydroxylase loss remains pathogenic to matrix structure despite survival.
    evidence:
    - reference: PMID:16467571
      reference_title: Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: Mice with a mutation that blocked only the LH activity of LH3 developed normally, but showed defects in the structure of the basement membrane and in collagen fibril organization in newborn skin and lung.
      explanation: Selective hydroxylase deficiency permits survival while still affecting basement membranes and fibril organization.
- name: mgtm635 plod3 Zebrafish
  species: Danio rerio
  genotype: Homozygous plod3 p.Gly245Glu (mgtm635)
  description: An ENU-derived missense model shows craniofacial, musculoskeletal, vascular, eye and ear abnormalities and early larval lethality. CRISPR exon-4 disruption phenocopies key defects. Human wild-type PLOD3 mRNA injected at the one-cell stage partially rescues the phenotype; tested clinical constructs have variable residual rescue. Autophagy-associated proteins and compartments increase, but these readouts do not by themselves quantify autophagic flux. Mitochondrial structural abnormalities and reduced metabolic transcripts do not establish a measured ATP deficit.
  publication: PMID:41827019
  evidence:
  - *id009
  - *id010
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: wild-type human PLOD3 mRNA partially rescued musculoskeletal, vascular, and brain phenotypes in zebrafish plod3 mutants
    explanation: Developmental mRNA rescue supports conservation of PLOD3 function; it is not evidence of human gene therapy.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: SA treatment significantly reduced the somite angle in treated animals by approximately 12%, trending towards WT levels
    explanation: A developmental treatment endpoint; human efficacy and post-onset rescue were not established.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: revealed accumulation of autophagy-related protein 5 (ATG5), p62 ... LC3-II ... and lysosomal enzyme cathepsin B
    explanation: The zebrafish study measured increased autophagy-associated markers; flux was not quantified by this observation alone.
  modeled_mechanisms:
  - target: Altered Extracellular Collagen Fibril Organization
    relationship: PARTIALLY_RECAPITULATES
    limitations: Early developmental cartilage model with severe larval disease; human tissue specificity and natural history differ.
    evidence:
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: surrounded by sparse extracellular matrix lacking collagen fibrils
      explanation: Transmission electron microscopy of mutant zebrafish cartilage showed deficient extracellular fibrillar matrix.
  - target: PERK Branch Unfolded Protein Response
    relationship: PARTIALLY_RECAPITULATES
    limitations: The stress response is measured; its role as harmful or adaptive is not resolved.
    evidence:
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: the PERK pathway was upregulated as shown by increased levels of its targets atf4 and ddit3 (Chop) in 4 dpf mgtm635 zebrafish
      explanation: The zebrafish model showed PERK-branch readouts, with corresponding phospho-eIF2α and Chop changes; the IRE1/ATF6 transcript readouts did not significantly change.
  notes: Succinate at 200 micromolar in egg water from 10 hours post-fertilization to four days improved body length and somite angle, with the angle reduced about 12%. Three metabolic transcripts approached wild-type levels; UPR transcript changes were not significant. This developmental experiment provides no human efficacy or safety evidence.
experimental_models:
- name: LH3-Knockout PFHR9 Cells
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  cell_source: Murine PFHR9 cell line, ATCC CRL-2423
  description: CRISPR disruption of Plod3 exons 5 and 7 in a collagen-IV-producing cell line reveals reduced type IV hydroxylation/glucosylation, abnormal triple helices and delayed secretion. Comparator commercial embryonic fibroblasts retained largely normal type I/III secretion despite decreased glucosylation.
  publication: PMID:36403858
  evidence:
  - *id011
  - *id012
  - *id007
  modeled_mechanisms:
  - target: Impaired Type IV and VI Collagen Secretion
    relationship: PARTIALLY_RECAPITULATES
    limitations: The experiment directly addresses type IV collagen in a murine cell line with high collagen-IV production, not every collagen or patient tissue.
    evidence:
    - reference: PMID:36403858
      reference_title: Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: only one-fourth of newly synthesized collagen α1α1α2(IV) was secreted even after 48 h in culture
      explanation: Pulse-chase experiments measured delayed and reduced secretion, rather than its complete absence.
- name: Patient-Derived PLOD3 Dermal Fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  cell_source: Dermal biopsy-derived fibroblasts carrying c.1354C>T with an in-frame splice product
  description: Patient fibroblasts were compared with unrelated BJ controls. RNA analysis identified p.Arg452_Val453del. Collagen I retention, distended ER, stress-response and autophagy-associated markers, and mitochondrial ultrastructural abnormalities were observed. The study did not use an isogenic corrected patient line or measure respiratory flux.
  publication: PMID:41827019
  evidence:
  - *id013
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: the c.1354 C > T transition created a premature GT splice donor site leading to a 6-bp in frame deletion
    explanation: Patient-derived RNA showed an in-frame deletion affecting Arg452 and Val453; a predicted stop-gain annotation does not describe the observed transcript.
  - reference: PMID:41827019
    reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: primary, patient-derived fibroblasts cultured under basal conditions showed a highly significant increase in ATG5, P62, LC3-I and LC3-II, and LAMP1
    explanation: Patient-derived fibroblasts also had increased autophagy-associated proteins. These marker levels do not prove increased degradative flux.
  modeled_mechanisms:
  - target: Collagen Retention in the Endoplasmic Reticulum
    relationship: PARTIALLY_RECAPITULATES
    limitations: A single patient-derived line with an unrelated control limits attribution of every difference to the variant.
    evidence:
    - reference: PMID:41827019
      reference_title: Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: COL1 (red) staining partially co-localized with ERp57 (ER marker; green)
      explanation: Patient fibroblast imaging supports collagen I retention in the endoplasmic reticulum; the comparison used an unrelated BJ fibroblast control.
- name: Recombinant LH3-COLGALT1 Complex
  experimental_model_type: OTHER
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  description: Purified recombinant proteins, cryo-EM and enzymatic assays define a 2:2 LH3-COLGALT1 complex and separate hydroxylase, galactosyltransferase and glucosyltransferase functions. Engineered interface substitutions can impair complex formation; this does not directly establish the effect of each patient allele.
  publication: PMID:40069201
  evidence:
  - reference: PMID:40069201
    reference_title: The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex
    explanation: The structural system identifies the multienzyme assembly.
  - reference: PMID:40240392
    reference_title: Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: DIRECT
    quote_role: PRIMARY_RESULT
    snippet: GLT25D1/COLGALT1 dimerization critically contributes to macromolecular complex formation with multifunctional LH3/PLOD3 enzymes.
    explanation: An independent structural and cross-linking study supports the complex interface.
  modeled_mechanisms:
  - target: Reduced Collagen Hydroxylysine Glucosylation
    relationship: MEASURES
    limitations: Wild-type and engineered recombinant systems define the normal machinery; variant-specific effects require direct testing.
    evidence:
    - reference: PMID:40069201
      reference_title: The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      directness: DIRECT
      quote_role: PRIMARY_RESULT
      snippet: The structures reveal a stoichiometry of 2:2 between the two enzymes in the LH3-ColGalT1 quaternary complex
      explanation: Cryo-EM and recombinant complex assays support coordinated modification by distinct enzymes.

📚

References & Deep Research

References

15

PMID:16467571

Glycosylation catalyzed by lysyl hydroxylase 3 is essential for basement membranes.

No top-level findings curated for this source.

PMID:17873278

Secretion and assembly of type IV and VI collagens depend on glycosylation of hydroxylysines.

No top-level findings curated for this source.

PMID:18834968

A connective tissue disorder caused by mutations of the lysyl hydroxylase 3 gene.

No top-level findings curated for this source.

PMID:27435297

Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis.

No top-level findings curated for this source.

PMID:30089812

Molecular architecture of the multifunctional collagen lysyl hydroxylase and glycosyltransferase LH3.

No top-level findings curated for this source.

PMID:30463024

Mutations in PLOD3, encoding lysyl hydroxylase 3, cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa-like blistering phenotype with abnormal anchoring fibrils and type VII collagen deficiency.

No top-level findings curated for this source.

PMID:31129566

Pathogenic variants in PLOD3 result in a Stickler syndrome-like connective tissue disorder with vascular complications.

No top-level findings curated for this source.

PMID:36203519

Cerebral small vessel disease caused by PLOD3 mutation: Expanding the phenotypic spectrum of lysyl hydroxylase-3 deficiency.

No top-level findings curated for this source.

PMID:36403858

Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).

No top-level findings curated for this source.

PMID:37446392

Identification of Regulatory Molecular "Hot Spots" for LH/PLOD Collagen Glycosyltransferase Activity.

No top-level findings curated for this source.

PMID:40069201

The structural basis for the human procollagen lysine hydroxylation and dual-glycosylation.

No top-level findings curated for this source.

PMID:40240392

Molecular structure and enzymatic mechanism of the human collagen hydroxylysine galactosyltransferase GLT25D1/COLGALT1.

No top-level findings curated for this source.

PMID:40289369

Expanding the Clinical Spectrum of BCARD Syndrome Caused by Novel Biallelic Variants in the PLOD3 Gene.

No top-level findings curated for this source.

PMID:41827019

Succinate supplementation ameliorates musculoskeletal defects caused by PLOD3 mutations in a BCARD syndrome model.

No top-level findings curated for this source.

url:https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf

https://kclpure.kcl.ac.uk/ws/files/103095648/Mutations_in_PLOD3_encoding_VAHIDNEZHAD_Firstonline18November2018_GREEN_AAM_CC_BY_NC_ND_.pdf

No top-level findings curated for this source.

Deep Research

1

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Evaluations and curation notes (1)

Create: Bone Fragility With Contractures Arterial Rupture And Deafness (BCARD) · 2026-09-14T21:40:08Z · View source

Created BCARD syndrome (PLOD3 / lysyl hydroxylase 3 deficiency) from the primary literature plus an OpenScientist deep-research report (11/11 references verified). Five-node chain from biallelic PLOD3 loss of function through loss of hydroxylysine-linked glycosylation and failure of type IV and VI collagen assembly and secretion to basement membrane failure and multisystem connective tissue fragility. The entry is framed as a collagen glycosylation disease rather than a hydroxylation disease, following the mouse genetics: a mouse blocked only in the lysyl hydroxylase activity develops normally, while reducing glucosyltransferase activity is embryonic-lethal in proportion to the residual level. Causal-chain evidence is therefore graded MODEL_ORGANISM, with human evidence anchoring the endpoints. Two discussions record open points: whether LH3 carries both glycosyltransferase activities or only the glucosyltransferase (a 2023 direct mass-spectrometry study contradicts the original indirect-assay assignment), and whether the epidermolysis-bullosa-like blistering is a rare feature of one syndrome or a distinct presentation. Phenotype frequencies are graded from where a feature appears in the literature rather than from counts, because no per-feature counts exist across the roughly eleven published patients. During curation just check-reference-titles caught a reference_title I had composed from the deep-research report's description rather than copied from the cache frontmatter (similarity 0.53); both occurrences were corrected from the cached title. Validated with just validate-disorders (28/28 snippets), just validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-reference-titles.

OpenScientist ▸

Bone Fragility With Contractures, Arterial Rupture and Deafness (BCARD Syndrome): A Comprehensive Disease Report

openscientist-autonomous 11 citations 2026-09-14T21:20:11.837948

Bone Fragility With Contractures, Arterial Rupture and Deafness (BCARD Syndrome): A Comprehensive Disease Report

Disease: Bone Fragility With Contractures, Arterial Rupture and Deafness (BCARD) MONDO ID: MONDO:0012892 · OMIM: #612394 · Gene: PLOD3 (LH3) Category: Mendelian (autosomal recessive connective-tissue disorder)

Summary

Bone fragility with contractures, arterial rupture and deafness (BCARD) is an ultra-rare, autosomal recessive, multisystem connective-tissue disorder caused by biallelic loss-of-function variants in PLOD3, the gene encoding the multifunctional collagen-modifying enzyme lysyl hydroxylase 3 (LH3). First described in a human patient in 2008, the disease remains exceptionally rare, with only approximately 11 patients across roughly seven reports documented as of 2025. It is catalogued as OMIM #612394 and MONDO:0012892, and its clinical description is derived almost entirely from aggregated case reports of individual patients rather than large registries.

The central molecular lesion is loss of LH3 enzymatic activity. LH3 is unusual among collagen-modifying enzymes because it is bifunctional: it performs lysyl hydroxylation of collagen lysine residues and the subsequent O-glycosylation (galactosylation and glucosylation) of the resulting hydroxylysines. Mouse genetics have established that the glucosyltransferase (GGT/Glc-T) activity — not the lysyl hydroxylase activity — is the function essential for basement-membrane formation, and that embryonic survival correlates directly with residual GGT activity. Loss of hydroxylysine glycosylation prevents the intracellular assembly and secretion of network and beaded-filament collagens (types IV and VI), producing widespread failure of basement membranes and extracellular matrix. This matrix failure explains the pleiotropic clinical picture: low bone mineral density and bone fragility, joint/finger contractures, cataract with retinal-detachment risk, sensorineural deafness, and life-threatening arterial aneurysm/dissection, together with variable skin fragility (an epidermolysis-bullosa-like phenotype), muscle ultrastructural changes overlapping Ullrich congenital muscular dystrophy, and — in the most severe cases — a devastating neurovascular phenotype (cerebral small-vessel disease, cortical malformations, epilepsy).

Diagnosis rests on exome/genome sequencing plus a supportive biochemical biomarker — markedly reduced glycosylated hydroxylysine (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) in tissue/fibroblasts, and reduced LH3 protein in skin. There is no disease-modifying therapy; management is symptomatic and multidisciplinary, with particular vigilance for vascular catastrophe. This report synthesizes nine confirmed findings and 25 reviewed papers to populate the disease knowledge-base entry across all requested domains, and flags where evidence is absent or extrapolated.

Key Findings

F001 — BCARD is an autosomal recessive connective-tissue disorder caused by biallelic PLOD3 (LH3) variants

BCARD (OMIM #612394; MONDO:0012892) is caused by biallelic pathogenic variants in PLOD3 (encoding lysyl hydroxylase 3, LH3; gene OMIM 603066; HGNC:9083; located on chromosome 7q22.1). The first patient, reported in 2008, was a compound heterozygote, establishing recessive inheritance. As of 2025 the literature describes only ~11 patients across ~7 reports, confirming ultra-rarity.

A 2025 review states plainly: "BCARD syndrome is a rare autosomal recessive connective tissue disorder characterized by bone abnormalities, cataract, risk of arterial rupture due to vascular aneurisms or dissections, and sensorineural deafness" and that "BCARD, linked to biallelic pathogenic variants in the PLOD3 gene, was characterized in 10 cases across six reports" (PMID: 40289369). The original human report describes "a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance" (PMID: 18834968).

F002 — LH3/PLOD3 is a multifunctional collagen-modifying enzyme whose glycosyltransferase activity is essential for basement-membrane collagen secretion

LH3 catalyzes lysyl hydroxylation and the subsequent O-glycosylation of hydroxylysines (galactosyl- and glucosylgalactosyl-hydroxylysine) on collagens. Critically, mouse genetics demonstrate that the glucosyltransferase (GGT) activity, not the lysyl hydroxylase activity, is the function essential for basement-membrane formation: LH3-knockout and GGT-null hypomorphic embryos die at E9.5–E14.5 from failed basement-membrane formation, and embryonic survival correlates directly with the level of GGT activity. Loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and impairs secretion of types IV and VI collagen. Recent enzymology (2023) refines the division of labor, showing LH3 carries the Glc-T activity while GLT25D1 provides the Gal-T activity.

Key evidence: "the GGT activity, not the LH activity of LH3, is essential for the formation of the basement membrane" and "survival of hypomorphic embryos and the formation of the basement membrane were directly correlated with the level of GGT activity" (PMID: 16467571); "loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and leads to impaired secretion of type IV and VI collagens" (PMID: 17873278); and "LH3/PLOD3 only has Glc-T activity and that GLT25D1 only has Gal-T activity" (PMID: 37446392).

F003 — BCARD presents as a multisystem phenotype overlapping Stickler, Ehlers-Danlos and epidermolysis bullosa

Cardinal features span multiple organ systems: skeletal (low bone mineral density/bone fragility, scoliosis, prominent knees, finger/joint contractures), ocular (cataract, high myopia, retinal-detachment risk), auditory (sensorineural hearing loss), vascular (aneurysms/dissection, risk of arterial rupture), plus craniofacial dysmorphism, reduced palmar creases, and developmental delay. Some patients show a recessive dystrophic epidermolysis bullosa (RDEB)-like sub-lamina-densa skin blistering with abnormal anchoring fibrils and reduced type VII collagen. The 2025 expansion added vesico-ureteral reflux, intestinal and cardiac anomalies, focal epilepsy, and brain malformations (polymicrogyria, heterotopia). The overall phenotype overlaps most with Stickler syndrome, with variable EDS and EB features.

Supporting quotes: "Key clinical features included ocular abnormalities with risk for retinal detachment, sensorineural hearing loss, reduced palmar creases, finger contractures, prominent knees, scoliosis, low bone mineral density, recognisable craniofacial dysmorphisms, developmental delay and risk for vascular dissection" and "Collated clinical features showed most overlap with Stickler syndrome with variable features of Ehlers-Danlos syndrome (EDS) and epidermolysis bullosa (EB)" (PMID: 31129566); "The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of anchoring fibrils. The level of type VII collagen expression in the skin was markedly reduced" (PMID: 30463024); "also exhibited vesico-ureteral reflux, intestinal anomaly, minor cardiac anomalies, focal epilepsy, and brain abnormalities, including polymicrogyria and heterotopia" (PMID: 40289369).

F004 — LH3/PLOD3 molecular structure maps disease mutations near catalytic sites

Full-length human LH3 crystal structures reveal an elongated homodimer with two distinct catalytic sites — an N-terminal glycosyltransferase domain and a C-terminal lysyl hydroxylase/dioxygenase domain — separated by an accessory domain. Known disease-related mutations map in close proximity to the catalytic sites, and specific variants selectively abolish either the lysyl hydroxylase or the glycosyltransferase activity, accompanied by reduced LH3 protein levels in patient cells.

Evidence: "The elongated homodimeric LH3 architecture shows two distinct catalytic sites at the N- and C-terminal boundaries of each monomer, separated by an accessory domain" and "Known disease-related mutations map in close proximity to the catalytic sites" (PMID: 30089812); "One mutation dramatically reduced the sugar-transfer activity of LH3, whereas another abrogated lysyl hydroxylase activity; these changes were accompanied by reduced LH3 protein levels in cells" (PMID: 18834968).

F005 — Post-Golgi trafficking of LH3 is required for collagen glycosylation homeostasis, linking BCARD to ARC syndrome biology

LH3 acts partly extracellularly / post-Golgi. VIPAR (VIPAS39) together with VPS33B sorts LH3 into newly identified post-Golgi collagen-IV carriers, and this sorting is essential for lysine modification of multiple collagen types. Loss of VIPAR/VPS33B — which causes Arthrogryposis–Renal dysfunction–Cholestasis (ARC) syndrome — produces collagen abnormalities mirroring those of primary LH3 deficiency, connecting the two disorders mechanistically.

Evidence: "VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types" and "regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues" (PMID: 27435297).

F006 — Reduced glycosylated hydroxylysine is the biochemical hallmark and candidate diagnostic biomarker

Patient tissue/fibroblast analyses show markedly reduced glycosylated hydroxylysine — specifically galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine — together with dramatically reduced LH3 protein in skin and fibroblast cultures. LH3 normally localizes to the epidermal basement membrane and is severely depleted there in patients, making immunostaining a complementary diagnostic modality.

Evidence: "Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine" and "The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient" (PMID: 30463024); "We show abundant LH3 localising to the basement membrane in normal skin which is severely depleted in RDEB patient skin" (PMID: 26380979).

F007 — PLOD3/LH3 deficiency includes a severe neurovascular phenotype

A homozygous in-frame variant c.1216_1218delCTC (p.Leu406del) caused an infantile-onset (10 months) severe phenotype: developmental delay, clustered epileptic spasms with hypsarrhythmia (West syndrome), and MRI showing multiple intracranial malacias, bleeding foci, extensive white-matter abnormalities and brain atrophy consistent with cerebral small-vessel disease (SVD), plus flattened vertebrae and metacarpal abnormalities. The 2025 case added polymicrogyria, heterotopia and focal epilepsy. Craniofacial dysmorphism (hypertelorism, upturned nose, low-set ears) was noted.

Evidence: "Cerebral magnetic resonance imaging showed multiple intracranial malacias and bleeding foci, extensive abnormal signals in the white matter, and obvious brain atrophy, which was consistent with cerebral small vessel disease (SVD)" and "Whole-exome sequencing revealed a novel homozygous variant of c.1216_1218delCTC (p.L406del)" (PMID: 36203519); "brain abnormalities, including polymicrogyria and heterotopia" (PMID: 40289369).

F008 — gnomAD constraint metrics confirm PLOD3 is not haploinsufficient, consistent with recessive disease

gnomAD (GRCh38) constraint for PLOD3 (ENSG00000106397; chr7:101,205,977–101,218,420; 7q22.1) shows pLI ≈ 0 (6.4e-19), LoF observed/expected = 0.75 (73 observed vs 96.9 expected LoF variants), LOEUF = 0.92, and missense Z ≈ 0.004 (oe_mis ≈ 1.0). Heterozygous loss-of-function is therefore tolerated in the general population, matching the observed autosomal recessive (biallelic) inheritance. This is consistent with the human report of "a human disorder of LH3 presenting as a compound heterozygote with recessive inheritance" (PMID: 18834968).

F009 — LH3 deficiency produces collagen VI muscle ultrastructural changes overlapping Ullrich congenital muscular dystrophy

In LH3-manipulated mice, altered distribution and aggregation of type VI collagen produced muscle ultrastructural alterations similar to those in collagen VI knockout mice and some Ullrich congenital muscular dystrophy patients. Underglycosylated types IV and VI collagen showed abnormal distribution. Evidence: "The altered distribution and aggregation of type VI collagen led to similar ultrastructural alterations in muscle to those detected in collagen VI knockout and some Ullrich congenital muscular dystrophy patients" (PMID: 17873278).

Section-by-Section Disease Characterization

1. Disease Information

BCARD is a rare autosomal recessive connective-tissue disorder defined by the combination of bone abnormalities/fragility, joint contractures, cataract, risk of arterial rupture (aneurysm/dissection), and sensorineural deafness (PMID: 40289369).

Key identifiers: | Resource | Identifier | |---|---| | OMIM (disease) | #612394 | | OMIM (gene PLOD3) | 603066 | | MONDO | MONDO:0012892 | | HGNC | HGNC:9083 (PLOD3) | | Ensembl gene | ENSG00000106397 | | Cytoband | 7q22.1 |

Synonyms / alternative names: "Bone fragility with contractures, arterial rupture, and deafness"; "BCARD syndrome"; "PLOD3-related connective tissue disorder"; "Lysyl hydroxylase 3 (LH3) deficiency." Orphanet, ICD-10/ICD-11, and MeSH do not maintain a dedicated, widely-cited term distinct from the OMIM/MONDO entries; the condition is best indexed via OMIM #612394 and the gene PLOD3.

Source of information: Derived almost exclusively from aggregated individual case reports (~11 patients / ~7 reports), not EHR-scale or registry data.

2. Etiology

Primary cause: Purely genetic — biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic variants in PLOD3 (F001, F004). No environmental or infectious cause exists.

Genetic risk factors: The disease-causing variants are the only known genetic determinant. Because PLOD3 is not haploinsufficient (pLI ≈ 0, LOEUF 0.92; F008), carriers (heterozygotes) are unaffected, and disease requires two damaging alleles. Consanguinity is a relevant contributor because homozygous variants (e.g., p.Leu406del) have been reported (F007).

Environmental / lifestyle / infectious factors, protective factors, gene-environment interactions: No environmental risk or protective factors, and no gene–environment interactions, are established for this Mendelian disorder. Clinically, avoidance of vascular stressors is prudent given arterial fragility, but this is inferred, not evidence-based.

3. Phenotypes

Phenotype	Type	Suggested HPO	Onset / severity / frequency notes
Low bone mineral density / bone fragility	Skeletal sign	HP:0004349 / HP:0002659	Congenital-early; core feature
Joint / finger contractures	Physical manifestation	HP:0002803 / HP:0009473	Early; core
Scoliosis	Skeletal sign	HP:0002650	Childhood
Prominent knees	Physical	HP:0002815 (knee-related)	Core
Cataract	Ocular sign	HP:0000518	Congenital/early; core
High myopia	Ocular	HP:0011003	Variable
Retinal detachment (risk)	Ocular	HP:0000541	Risk feature
Sensorineural hearing loss	Auditory	HP:0000407	Core
Arterial aneurysm / dissection / rupture	Vascular	HP:0002616 / HP:0004942	Life-threatening; variable onset
Reduced palmar creases	Physical	HP:0010490	Recognizable sign
Craniofacial dysmorphism	Physical	HP:0001999	Core
Developmental delay	Neurodevelopmental	HP:0001263	Variable
Skin blistering (EB-like)	Skin	HP:0008066	Variable subphenotype
Vesico-ureteral reflux	Renal	HP:0000076	Expanded (2025)
Focal epilepsy / epileptic spasms	Neurological	HP:0007359 / HP:0011097	Severe cases
Polymicrogyria / heterotopia	CNS malformation	HP:0002126 / HP:0002282	Severe cases

Frequencies cannot be quantified precisely given ~11 patients. Severity is variable, ranging from a Stickler-like presentation to lethal infantile neurovascular disease (F003, F007). Progression is generally stable-to-progressive with episodic vascular risk. Quality-of-life impact is substantial: sensory (vision, hearing), mobility (contractures, bone fragility), neurodevelopmental disability, and the constant threat of vascular catastrophe. No disease-specific QoL instruments (EQ-5D/SF-36) have been applied to this ultra-rare cohort.

4. Genetic / Molecular Information

Causal gene: PLOD3 (LH3), OMIM 603066, HGNC:9083, chr 7q22.1 (F001). Inheritance: autosomal recessive.

Pathogenic variants: Reported variants include compound-heterozygous missense/functional variants in the founding case (one abrogating glycosyltransferase activity, another abrogating lysyl hydroxylase activity; F004), and the homozygous in-frame deletion c.1216_1218delCTC (p.Leu406del) in the severe neurovascular case (F007). Variant types span missense, in-frame deletion, and loss-of-function alleles. Functionally, variants cause loss of function — either selectively ablating one of LH3's two catalytic activities or reducing overall protein level (F004). Disease-related mutations cluster near the catalytic sites in the LH3 structure (F004).

Allele frequency / population data: Consistent with recessive disease, gnomAD shows LoF is tolerated (73 observed vs 96.9 expected; LOEUF 0.92); no common pathogenic allele reaches appreciable frequency (F008). Origin: germline. Modifier genes / epigenetics / chromosomal abnormalities: none established; trafficking partners VPS33B/VIPAR functionally modulate LH3 activity and, when mutated, cause the related ARC syndrome (F005).

5. Environmental Information

No environmental factors, lifestyle factors, or infectious agents contribute to BCARD. It is a monogenic disorder (F001, F002). This section is not applicable beyond noting that mechanical/vascular stress may precipitate complications (rupture) in already-fragile tissue (inferred).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic PLOD3 loss-of-function variants lead to reduced/absent functional LH3 enzyme (and reduced LH3 protein levels) (F001, F004).
Loss of LH3 results in deficient lysyl hydroxylation and, critically, deficient glucosyltransferase (GGT/Glc-T)-mediated O-glycosylation of collagen hydroxylysines (F002).
Loss of glycosylated hydroxylysines prevents the intracellular tetramerization of type VI collagen and impairs secretion of type IV and type VI collagens (F002).
Impaired secretion/assembly leads to failure of basement-membrane formation and defective extracellular matrix (demonstrated in mouse: BM formation and embryo survival scale with residual GGT activity) (F002).
[Branch — trafficking] LH3 must be sorted into post-Golgi collagen-IV carriers by VPS33B/VIPAR; if this axis fails, the same collagen-modification defect ensues (links BCARD to ARC syndrome) (F005).
Matrix failure manifests in a tissue-specific manner:
Bone/connective tissue → bone fragility, contractures, scoliosis (inferred from collagen/matrix defect).
Basement-membrane-dependent structures (lens, cochlea, vessel wall) → cataract, sensorineural deafness, arterial aneurysm/rupture (inferred from BM collagen IV failure).
Skin (anchoring fibrils, type VII collagen reduced) → EB-like sub-lamina-densa blistering (F003, F006).
Muscle (collagen VI mis-aggregation) → Ullrich-CMD-like ultrastructural change (F009).
CNS microvasculature → cerebral small-vessel disease, hemorrhage, cortical malformation, epilepsy in severe cases (F007).

Upstream vs downstream: The mutation and enzymatic loss are upstream; collagen underglycosylation and secretion failure are the pivotal intermediate node; organ-specific matrix failure is downstream. Molecular pathway: collagen biosynthesis / post-translational modification (hydroxylysine formation and O-glycosylation). GO term suggestions: peptidyl-lysine hydroxylation (GO:0017185), collagen fibril organization (GO:0030199), basement membrane organization (GO:0071711), collagen-containing extracellular matrix (GO:0062023, cellular component), protein glycosylation (GO:0006486). CL/cell types: fibroblast (CL:0000057), osteoblast (CL:0000062), vascular smooth muscle cell (CL:0000359), keratinocyte (CL:0000312). CHEBI entities: hydroxylysine (CHEBI:24544-class), galactosylhydroxylysine, glucosylgalactosylhydroxylysine, UDP-glucose (CHEBI:46229), UDP-galactose, 2-oxoglutarate (CHEBI:16810). Subcellular compartments: endoplasmic reticulum and Golgi (GO:0005783, GO:0005794) for collagen modification/secretion; post-Golgi carriers/extracellular space for LH3 trafficking (F005).

7. Anatomical Structures Affected

Primary organs / systems: skeleton (UBERON:0002481 bone tissue), eye/lens (UBERON:0000965 lens), inner ear/cochlea (UBERON:0001844), arteries/vascular system (UBERON:0001637; cardiovascular system UBERON:0004535), skin (UBERON:0002097), skeletal muscle (UBERON:0001134), and — in severe cases — brain (UBERON:0000955) and cerebral small vessels. Secondary: kidney/urinary tract (vesico-ureteral reflux), gastrointestinal tract, and heart (minor anomalies) (F003).

Tissue/cell level: connective tissue and basement membranes are the unifying target; affected cell populations include fibroblasts, osteoblasts, vascular smooth-muscle cells, keratinocytes, and CNS vascular cells (F002, F003, F007, F009). Subcellular: ER/Golgi secretory pathway and post-Golgi trafficking (F005). Lateralization: systemic/bilateral.

8. Temporal Development

Onset: congenital-to-infantile; the severe neurovascular form presented at 10 months (F007). Pattern: chronic with a superimposed episodic risk of acute vascular events (dissection/rupture) and, in severe cases, epileptic spasms. Progression: variable — from a relatively stable Stickler-like course to rapidly progressive infantile encephalopathy with brain atrophy (F007). Critical periods: early development (basement-membrane formation is embryonically essential in mouse models; F002) and any period of vascular stress. Duration: lifelong.

9. Inheritance and Population

Inheritance: autosomal recessive (F001, F008). Epidemiology: ultra-rare; no formal prevalence/incidence estimate exists — only ~11 patients reported worldwide (F001). Penetrance: appears complete in biallelic carriers, though expressivity is highly variable (F003, F007). Consanguinity contributes (homozygous variants reported). Carrier frequency: not formally established; gnomAD LoF tolerance indicates carriers are asymptomatic and present in the general population (F008). Founder effects, anticipation, germline mosaicism: none reported. Sex ratio / ethnicity / geography: no demonstrated bias; cases are geographically scattered.

10. Diagnostics

Genetic testing is the definitive diagnostic modality. Given the multisystem, Stickler/EDS/EB-overlapping phenotype, whole-exome or whole-genome sequencing (or a connective-tissue/collagenopathy gene panel including PLOD3) is the recommended approach; single-gene testing is appropriate when the phenotype is recognized (F003).

Biochemical biomarker: reduced glycosylated hydroxylysine (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) in tissue/fibroblasts, with reduced LH3 protein — a supportive, mechanism-specific assay (F006). Immunohistochemistry of skin shows severe basement-membrane LH3 depletion (F006). Imaging: DXA (low BMD), skeletal radiographs (flattened vertebrae, metacarpal changes), vascular imaging (CT/MR angiography for aneurysm/dissection surveillance), ophthalmologic exam (cataract, myopia, retinal detachment), audiometry (sensorineural loss), and brain MRI in neurological cases (SVD, malformations) (F003, F007). Skin biopsy/EM in blistering cases shows sub-lamina-densa cleavage, abnormal anchoring fibrils, reduced type VII collagen (F003, F006).

Differential diagnosis: Stickler syndrome (closest overlap), Ehlers-Danlos syndromes, epidermolysis bullosa, Ullrich congenital muscular dystrophy, and ARC syndrome (VPS33B/VIPAR) (F003, F005, F009).

11. Outcome / Prognosis

Prognosis is guarded and variable. The most serious threat is arterial rupture/dissection, a potentially fatal complication (F001, F003). The severe infantile neurovascular form carries a poor prognosis with cerebral small-vessel disease, hemorrhage, brain atrophy, and refractory epileptic spasms (F007). Morbidity is high across sensory (vision, hearing), musculoskeletal (fragility, contractures), and neurodevelopmental domains. No formal survival statistics exist due to rarity. Prognostic factors (inferred): earlier onset and neurovascular involvement predict worse outcomes. No validated prognostic biomarkers exist beyond the mechanistic biochemical markers.

12. Treatment

No disease-modifying therapy exists. Management is symptomatic and multidisciplinary (NCIT suggestions: Supportive Care Intervention, Physical Therapy, Surgical Procedure, Genetic Counseling): - Vascular: surveillance imaging and prophylactic/emergency vascular surgery for aneurysm/dissection; avoidance of vascular stress (inferred best practice given rupture risk). - Skeletal: management of low BMD and fractures; orthopedic care for scoliosis/contractures; physical and occupational therapy. - Ophthalmologic: cataract surgery, myopia correction, retinal-detachment monitoring/repair. - Auditory: hearing aids / cochlear implantation for sensorineural loss. - Neurological: anti-seizure medication for epileptic spasms/focal epilepsy; developmental support. - Dermatologic: wound care for EB-like blistering.

Pharmacogenomics, gene/cell/RNA therapy, targeted/immunotherapy: none established or in trials for BCARD specifically. Experimental therapeutics: no registered clinical trials identified for this disease.

13. Prevention

There is no primary prevention for this Mendelian disorder beyond reproductive genetic counseling. Given autosomal recessive inheritance and a role for consanguinity, carrier testing of at-risk relatives, cascade testing, and options such as prenatal diagnosis or preimplantation genetic testing are appropriate for families with a known variant (F001, F008). Secondary/tertiary prevention focuses on surveillance (vascular imaging, ophthalmology, audiology, DXA) and prompt intervention to prevent catastrophic complications, especially arterial rupture (F003). NCIT suggestion: Genetic Counseling, Prenatal Diagnosis.

14. Other Species / Natural Disease

PLOD3 is evolutionarily conserved; the mouse ortholog Plod3 provides the key mechanistic models (F002, F009). No naturally occurring companion-animal or wildlife BCARD-equivalent disease is documented in OMIA. There is no zoonotic or transmission relevance (monogenic disorder). Orthologs exist across vertebrates (human PLOD3 NCBI Gene 8985; mouse Plod3), supporting cross-species mechanistic study.

15. Model Organisms

The principal model is the mouse (Mus musculus): - LH3/Plod3 knockout embryos die at E9.5 from failed basement-membrane formation (F002). - GGT-null hypomorphic embryos die E9.5–E14.5, with survival scaling to residual GGT activity — establishing the glucosyltransferase activity as the essential function (F002). - LH3-manipulated mice reproduce collagen VI muscle ultrastructural pathology overlapping Ullrich CMD (F009).

Phenotype recapitulation: mouse models faithfully capture the core molecular lesion (collagen underglycosylation, BM failure) and muscle pathology; limitation: complete knockouts are embryonic-lethal, so hypomorphic/conditional models are required to study postnatal, organ-specific human features (bone, ear, vessel, brain). Cellular models — patient fibroblasts — recapitulate reduced glycosylated hydroxylysine and reduced LH3 protein (F006), and the VPS33B/VIPAR (ARC syndrome) system provides complementary in vitro/murine models of the trafficking arm (F005). No zebrafish, Drosophila, or iPSC/organoid BCARD models are documented in the reviewed literature.

Mechanistic Model / Interpretation

 Biallelic PLOD3 (LH3) LoF variants
      │  (F001, F004; variants cluster near catalytic sites)
      ▼
 Loss of LH3 lysyl-hydroxylase AND glucosyltransferase (GGT) activity
      │  (F002; GGT activity is the essential one)
      ▼
 Deficient O-glycosylation of collagen hydroxylysines
   (↓ galactosyl-Hyl, ↓ glucosyl-galactosyl-Hyl)  ◄── DIAGNOSTIC BIOMARKER (F006)
      │
      ▼
 Failed intracellular assembly (Col VI tetramerization) +
 impaired secretion of type IV & VI collagens              (F002)
      │
      ┌───────┴─────────────────────────────┐
      ▼                                       ▼
 Basement-membrane failure            Post-Golgi trafficking dependency
 (embryonically essential in mouse)   via VPS33B/VIPAR — shared with
      │                               ARC syndrome                (F005)
      ▼
 ORGAN-SPECIFIC MATRIX FAILURE
  ├─ Bone/joint → fragility, contractures, scoliosis
  ├─ Lens → cataract; retina → detachment risk
  ├─ Cochlea → sensorineural deafness
  ├─ Artery wall → aneurysm / dissection / RUPTURE  ◄── lethal risk
  ├─ Skin → EB-like sub-lamina-densa blistering (↓ Col VII)   (F003, F006)
  ├─ Muscle → Ullrich-CMD-like ultrastructure (Col VI)        (F009)
  └─ CNS microvessels → small-vessel disease, hemorrhage,
     cortical malformation, epilepsy (severe cases)           (F007)

The unifying interpretation is that BCARD is a "collagen post-translational modification disease." A single enzyme's bifunctional loss cripples the glycosylation step required to fold, assemble and secrete the network (type IV) and beaded-filament (type VI) collagens that build basement membranes and connective-tissue scaffolds throughout the body. Because these collagens are ubiquitous, the phenotype is pleiotropic and overlaps several better-known collagenopathies (Stickler, EDS, EB, Ullrich CMD) — a diagnostic pitfall that makes sequencing essential. The glucosyltransferase activity is the mechanistic linchpin, and the trafficking arm (VPS33B/VIPAR) explains the phenotypic kinship with ARC syndrome.

Evidence Base

PMID	Title (abbrev.)	Role in this report
40289369	Expanding the Clinical Spectrum of BCARD Syndrome…	Defines disease, AR inheritance, biallelic PLOD3, ultra-rarity; expands phenotype to renal/GI/cardiac/CNS (F001, F003, F007)
18834968	A connective tissue disorder caused by mutations of the LH3 gene	First human case; recessive/compound-het; variant-specific loss of each enzymatic activity (F001, F004, F008)
16467571	Glycosylation catalyzed by LH3 is essential for basement membranes	GGT activity is the essential function; dose-dependent embryo survival (F002)
17873278	Secretion and assembly of type IV and VI collagens depend on glycosylation…	Mechanism: loss of Hyl-glycosylation blocks Col VI tetramerization / Col IV,VI secretion; Ullrich CMD muscle overlap (F002, F009)
37446392	Regulatory "Hot Spots" for LH/PLOD glycosyltransferase activity	Enzymatic division of labor: LH3=Glc-T, GLT25D1=Gal-T (F002)
30089812	Molecular architecture of LH3	Homodimer, two catalytic sites; disease mutations near active sites (F004)
31129566	Pathogenic variants in PLOD3…	Clinical feature catalogue; Stickler/EDS/EB overlap (F003)
30463024	PLOD3 mutations cause RDEB-like blistering…	Skin phenotype; reduced glycosylated Hyl biomarker; reduced LH3 protein (F003, F006)
26380979	LH3 localizes to epidermal basement membrane…	LH3 BM localization/depletion; IHC diagnostic modality (F006)
36203519	Cerebral small vessel disease caused by PLOD3…	Severe neurovascular phenotype; homozygous p.Leu406del (F007)
27435297	Regulation of post-Golgi LH3 trafficking…	VPS33B/VIPAR sorting of LH3; ARC syndrome link (F005)

The remaining reviewed papers (e.g., PLOD3 in colorectal, lung, liver, bladder, esophageal cancers; PMIDs 39948137, 35265665, 35116582, 36872941, 41491166, 39659928, 34646265) concern PLOD3's oncologic/ECM-remodeling role and do not bear directly on BCARD pathophysiology; they are noted here only to document that LH3 also functions in tumor ECM stiffening — a context distinct from the germline loss-of-function disease.

Limitations and Knowledge Gaps

Ultra-rarity (n ≈ 11): All clinical conclusions rest on a handful of case reports. Frequencies, penetrance, expressivity, and prognosis cannot be quantified with confidence.
No epidemiological data: Prevalence, incidence, carrier frequency, sex/ethnic distribution are unknown.
Genotype–phenotype correlation is immature: Only a few variants are functionally characterized; whether specific alleles (e.g., GGT-selective vs LH-selective) predict organ-specific severity is unresolved.
Mechanistic inference for organ-specific features: The link from collagen underglycosylation to bone, ear, and vessel phenotypes is strongly plausible but largely inferred from collagen biology rather than directly demonstrated in BCARD tissue.
No therapeutics or trials: No disease-modifying therapy, no registered clinical trials, no validated QoL or prognostic instruments.
Model gaps: Complete-knockout embryonic lethality limits study of postnatal features; conditional/hypomorphic, zebrafish, and iPSC/organoid models are underdeveloped or absent.
Biomarker validation: Reduced glycosylated hydroxylysine is promising but not standardized as a clinical diagnostic assay across laboratories.

Proposed Follow-up Experiments / Actions

Establish an international BCARD/PLOD3 patient registry to aggregate the scattered cases and generate the first real prevalence, penetrance, natural-history, and mortality data — with structured vascular-event and neurodevelopmental outcomes.
Systematic genotype–phenotype study: functionally classify each reported PLOD3 variant for residual LH vs GGT activity (in vitro assays) and correlate with organ involvement and severity, testing the hypothesis that residual GGT activity predicts survival/severity (extending F002).
Standardize the biochemical diagnostic: validate a quantitative urinary/tissue glycosylated-hydroxylysine assay (ratio of glucosyl-galactosyl-Hyl to total Hyl) as a rapid, orthogonal confirmatory test alongside sequencing (F006).
Develop conditional/hypomorphic mouse and human iPSC-derived models (osteoblast, vascular smooth muscle, cochlear, cortical) to interrogate postnatal, tissue-specific mechanisms not accessible in embryonic-lethal knockouts (addressing F002/F007/F009 gaps).
Vascular surveillance protocol: define evidence-based imaging intervals and intervention thresholds for aneurysm/dissection, given rupture is the leading lethal risk (F003).
Explore trafficking-based therapeutic hypotheses: given the VPS33B/VIPAR–LH3 axis (F005), test whether enhancing LH3 stability/trafficking or supplying residual GGT activity rescues collagen glycosylation in patient fibroblasts — a first step toward any disease-modifying strategy.
Cross-collagenopathy differential-diagnosis panel: ensure PLOD3 is included in Stickler/EDS/EB/Ullrich-CMD gene panels so that BCARD is not missed in patients presenting with overlapping features (F003, F009).

Report compiled from 9 confirmed findings and 25 reviewed papers over 5 investigation iterations. Evidence types: human clinical case reports (PMIDs 40289369, 31129566, 30463024, 36203519, 18834968, 26380979); in vitro/structural (30089812, 37446392, 26380979); mouse model (16467571, 17873278); trafficking/cell biology (27435297); population genomics (gnomAD, supporting F008).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	11
Resolved	11
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	11
On topic	8
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	45
Resolved	41
Unresolved (possible confabulation)	0
Obsolete	3
Unverifiable	1
Terms whose name was checked	16
Terms named correctly	3
Terms named as a different term	10
Terms whose name is worth a second look	3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012892 (4 mentions) - the report calls it "MONDO"; MONDO calls it bone fragility with contractures, arterial rupture, and deafness
HP:0002650 (1 mention) - the report calls it "Skeletal sign"; HP calls it Scoliosis
HP:0002815 (1 mention) - the report calls it "knee-related"; HP calls it Abnormality of the knee
HP:0000518 (1 mention) - the report calls it "Ocular sign"; HP calls it Cataract
HP:0011003 (1 mention) - the report calls it "Ocular"; HP calls it High myopia
HP:0000541 (1 mention) - the report calls it "Ocular"; HP calls it Retinal detachment
HP:0000407 (1 mention) - the report calls it "Auditory"; HP calls it Sensorineural hearing impairment
HP:0010490 (1 mention) - the report calls it "Physical"; HP calls it Abnormal palmar crease morphology
HP:0001999 (1 mention) - the report calls it "Physical"; HP calls it Abnormal facial shape
HP:0000076 (1 mention) - the report calls it "Renal"; HP calls it Vesicoureteral reflux

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0062023 (obsolete collagen-containing extracellular matrix) (1 mention) - replaced by GO:0031012
GO:0006486 (obsolete protein glycosylation) (1 mention) - replaced by GO:0009101
CHEBI:24544 (CHEBI_24544) (1 mention) - replaced by CHEBI:15525

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001263 (1 mention) - the report calls it "Neurodevelopmental"; HP calls it Global developmental delay, and lists "Developmental delay" among its other names
HP:0008066 (1 mention) - the report calls it "Skin"; HP calls it Abnormal blistering of the skin, and lists "Skin bullae" among its other names
GO:0006486 (1 mention) - the report calls it "protein glycosylation"; GO calls it obsolete protein glycosylation

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References

Deep Research

Bone Fragility With Contractures, Arterial Rupture and Deafness (BCARD Syndrome): A Comprehensive Disease Report

Summary

Key Findings

F001 — BCARD is an autosomal recessive connective-tissue disorder caused by biallelic PLOD3 (LH3) variants

F002 — LH3/PLOD3 is a multifunctional collagen-modifying enzyme whose glycosyltransferase activity is essential for basement-membrane collagen secretion

F003 — BCARD presents as a multisystem phenotype overlapping Stickler, Ehlers-Danlos and epidermolysis bullosa

F004 — LH3/PLOD3 molecular structure maps disease mutations near catalytic sites

F005 — Post-Golgi trafficking of LH3 is required for collagen glycosylation homeostasis, linking BCARD to ARC syndrome biology

F006 — Reduced glycosylated hydroxylysine is the biochemical hallmark and candidate diagnostic biomarker

F007 — PLOD3/LH3 deficiency includes a severe neurovascular phenotype

F008 — gnomAD constraint metrics confirm PLOD3 is not haploinsufficient, consistent with recessive disease

F009 — LH3 deficiency produces collagen VI muscle ultrastructural changes overlapping Ullrich congenital muscular dystrophy

Section-by-Section Disease Characterization

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look