Cardiac-valvular Ehlers-Danlos syndrome (cvEDS) is an ultra-rare autosomal recessive connective tissue disorder associated with biallelic COL1A2 null variants and loss of the proalpha2(I) collagen chain. Nonsense, frameshift and splice-altering alleles can produce unstable transcripts; type I collagen is assembled as alpha1(I) homotrimers. Joint hypermobility, skin hyperextensibility and tissue fragility accompany progressive mitral and/or aortic valve disease, which may be inconspicuous in childhood. Valve replacement has been successful in some patients, but severe procedural tissue fragility is also documented. Most well-characterized null cases lack the recurrent fractures of osteogenesis imperfecta; reduced bone density and overlapping COL1A2 phenotypes require a qualified differential diagnosis. Molecular confirmation and continuing echocardiographic surveillance are important even with a mild childhood presentation.
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name: Cardiac Valvular Ehlers-Danlos Syndrome
category: Mendelian
creation_date: "2026-07-31T00:00:00Z"
description: >-
Cardiac-valvular Ehlers-Danlos syndrome (cvEDS) is an ultra-rare autosomal recessive connective tissue disorder
associated with biallelic COL1A2 null variants and loss of the proalpha2(I) collagen chain. Nonsense, frameshift
and splice-altering alleles can produce unstable transcripts; type I collagen is assembled as alpha1(I) homotrimers.
Joint hypermobility, skin hyperextensibility and tissue fragility accompany progressive mitral and/or aortic
valve disease, which may be inconspicuous in childhood. Valve replacement has been successful in some patients,
but severe procedural tissue fragility is also documented. Most well-characterized null cases lack the recurrent
fractures of osteogenesis imperfecta; reduced bone density and overlapping COL1A2 phenotypes require a qualified
differential diagnosis. Molecular confirmation and continuing echocardiographic surveillance are important
even with a mild childhood presentation.
disease_term:
preferred_term: cardiac valvular Ehlers-Danlos syndrome
term:
id: MONDO:0009159
label: Ehlers-Danlos syndrome, cardiac valvular type
synonyms:
- cvEDS
- cardiac-valvular EDS
- EDS, cardiac valvular type
- COL1A2-related Ehlers-Danlos syndrome, cardiac valvular type
- EDSCV
parents:
- Ehlers-Danlos Syndrome
- Connective Tissue Disorder
inheritance:
- name: Autosomal recessive inheritance
description: >-
Autosomal recessive inheritance with homozygous or compound heterozygous COL1A2 null alleles. Reported
mechanisms include nonsense, frameshift and splice-altering variants. Obligate carriers in reported families
were often clinically normal, although mild joint laxity was described in relatives in the founding series;
heterozygosity is not itself diagnostic of cvEDS. The 2017 review presumed complete penetrance, without
a measured penetrance estimate.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:15077201
reference_title: "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified three unrelated individuals with a rare recessively inherited form of EDS (characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects); in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon."
explanation: Documents both recessive genotype configurations in the founding case series.
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2."
explanation: An affected sibling pair homozygous for a nonsense variant, consistent with recessive segregation.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both parents were clinically normal. There was no history of fractures or dislocations, and they presented
no joint hypermobility.
explanation: >-
Parents of the child with a homozygous frameshift were heterozygous and clinically unaffected.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Obligate carriers displayed no overt symptoms. Penetrance is presum- ably complete.
explanation: >-
The 2017 review describes clinically unaffected obligate carriers and presumes complete penetrance; penetrance
was not quantified in a population cohort.
quote_role: REVIEW_SYNTHESIS
prevalence:
- population: Worldwide reported cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
The 2019 report described two sisters in addition to five previously molecularly confirmed patients. This
is a dated literature count, not a present-day total or a population prevalence estimate. Older reviews
grouped some COL1A2-deficient EDS/OI overlap cases together, so their denominators are not interchangeable.
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Only five molecularly confirmed patients have been reported to date."
explanation: >-
Number reported before the two additional sisters in the 2019 publication, not the current worldwide
count.
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Homozygous or compound heterozygous COL1A2 mutations resulting in complete deficiency of the proalpha2(I) collagen chains are extremely rare and have been reported in only a few patients, albeit with variable phenotypic outcome."
explanation: Independently confirms the extreme rarity of the causal genotype.
progression:
- phase: Childhood hypermobility-predominant phase
age_range: Childhood
notes: >-
Joint hypermobility and skin hyperextensibility may dominate childhood. The molecularly characterized six-year-old
boy had mitral valve bulging without gross mitral or aortic abnormalities, so absence of severe childhood
valve disease does not exclude cvEDS.
evidence:
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In this report we show that complete lack of proalpha2(I) collagen chains can present as a phenotype reminiscent of mild hypermobility EDS during childhood."
explanation: Documents the childhood hypermobility-like phase that precedes recognizable valve disease.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Echocardiography was performed and revealed no gross mitral or aortic valve abnormalities, although there
were signs of mitral valve bulging.
explanation: >-
The childhood cardiac examination was not entirely normal.
- phase: Progressive valvular disease
age_range: Adolescence to adulthood
notes: >-
Clinically important mitral and/or aortic insufficiency may develop in adulthood. The 2019 series described
mitral-first progression, but the founding series also included aortic-only disease; a universal valve
sequence is not established. Annual echocardiography is recommended in the 2017 rare-type review.
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "progressive heart valve disease firstly affecting the mitral valve"
explanation: >-
Reports mitral-first progression in the 2019 clinical synthesis; this does not establish a universal
sequence for all affected individuals.
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "careful cardiac follow up with ultrasonography is highly recommended because of the risk for cardiac valvular problems in adulthood"
explanation: Places the emergence of clinically significant valve disease in adulthood.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
in the other two either the aortic valve (brother of P3) or the mitral valve (P2) was involved.
explanation: >-
The founding report documents variable valve involvement.
pathophysiology:
- name: COL1A2 splice-altering variants
biological_scale: MOLECULAR
description: >-
Compound heterozygous splice-altering single-nucleotide variants in the founding cases affected donor sites
in introns 11 and 24 or activated an intron-1 cryptic exon. These are distinct sequence alterations from
nonsense and frameshift variants.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In P2, one allele harbored an A→G transition in intron 1 (IVS1+717A→G) that activated a cryptic exon
and led to inclusion of a 105-nt exon that contained four in-frame PTCs.
explanation: >-
Patient-cell sequence analysis identifies cryptic-exon inclusion.
genetic_context:
allele_type: SNV
zygosity: COMPOUND_HETEROZYGOUS
variant_origin: GERMLINE
variant_type: single nucleotide variant
downstream:
- target: Aberrant COL1A2 splicing
description: >-
The splice variants alter processing of patient fibroblast transcripts.
causal_link_type: DIRECT
- name: Aberrant COL1A2 splicing
biological_scale: MOLECULAR
description: >-
Cryptic donor use retains intronic sequence or truncates an exon; intron-1 pseudoexon inclusion provides
another route to premature termination codons. Local intron-removal order helps explain why the studied
donor variants do not simply skip an in-frame collagen exon. RNA-folding predictions are a possible explanation
for site choice, not direct evidence of in vivo RNA structure.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature
termination codon, and extremely unstable mRNA.
explanation: >-
Measured splice products and transcript instability in cultured dermal fibroblasts.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
These findings suggest that the order of intron removal is an important variable in prediction of mutation
outcome at splice sites
explanation: >-
Experimental splicing-order analysis supports context dependence.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: >-
It is conceivable that the spatial proximity between cryptic donor site and acceptor site, caused by
either donor-site mutation, promotes spliceosome access and cryptic splice site use.
explanation: >-
mfold modeling motivates a hypothesis about splice-site proximity.
cell_types: &id001
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
downstream:
- target: COL1A2 transcript depletion
description: >-
Premature stops in the abnormal transcripts engage nonsense-mediated decay.
causal_link_type: DIRECT
- name: COL1A2 nonsense variant
biological_scale: MOLECULAR
description: >-
Homozygous c.3601G>T, p.Glu1201Ter (reported as E1201X), was found in the founding brothers and later in
two affected sisters. The source associates this genotype with unstable COL1A2 transcripts.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A homozygous point mutation (c.3601G→T) in exon 50 of COL1A2 (fig. 3C) resulted in substitution of a
nonsense codon for glutamic acid (E1201X).
explanation: >-
Defines the founding nonsense allele.
- reference: PMID:30821104
reference_title: Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant
in COL1A2.
explanation: >-
Recurrence of the reported allele in another family.
genetic_context:
allele_type: SNV
zygosity: HOMOZYGOUS
variant_origin: GERMLINE
variant_type: single nucleotide variant
downstream:
- target: COL1A2 transcript depletion
description: >-
The premature stop is associated with very low mutant-transcript abundance.
causal_link_type: DIRECT
- name: COL1A2 frameshift insertion
biological_scale: MOLECULAR
description: >-
The 2006 child carried a homozygous single-C insertion reported as c.292_293insC, with an immediate downstream
premature termination codon. Both parents carried the insertion heterozygously. The legacy source notation
is retained without assigning an unreported transcript accession.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The resulting frameshift introduces a premature termination codon (PTC) in the next amino acid position.
explanation: >-
Sequencing identified a homozygous one-base insertion in exon 7, reported in the preceding sentence as
c.292_293insC.
genetic_context:
allele_type: INDEL
zygosity: HOMOZYGOUS
variant_origin: GERMLINE
variant_type: insertion
downstream:
- target: COL1A2 transcript depletion
description: >-
Downstream RT-PCR did not detect the affected child's COL1A2 cDNA.
causal_link_type: DIRECT
- name: COL1A2 transcript depletion
biological_scale: MOLECULAR
description: >-
Nonsense-mediated decay of premature-stop-containing COL1A2 transcripts markedly reduces their abundance
in patient dermal fibroblasts. This is RNA instability rather than demonstrated transcriptional silencing.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The amount of the transcripts from the mutant alleles was extremely low
explanation: >-
Mixing experiments demonstrate markedly depleted mutant transcripts.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
mRNA was shown to be markedly decreased.
explanation: >-
The 2006 discussion summarizes reduced COL1A2 transcript abundance in EDS-phenotype cases. Direct patient-fibroblast
evidence is supplied separately by the 2004 report.
quote_role: REVIEW_SYNTHESIS
cell_types: *id001
biological_processes:
- preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
term:
id: GO:0000184
label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
modifier: INCREASED
downstream:
- target: Loss of proalpha2(I) collagen chains
description: >-
Marked depletion of transcript removes the template for normal proalpha2(I) production.
causal_link_type: DIRECT
- name: Loss of proalpha2(I) collagen chains
biological_scale: MOLECULAR
description: >-
Patient fibroblasts synthesize no detectable proalpha2(I) chain. Loss of this type I collagen component
removes its contribution to extracellular matrix tensile structure; this annotation names the normal molecular
role lost and does not claim a measured quantitative change in whole-tissue tensile strength.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The cells from P1, P2, and P3 synthesized no detectable amounts of the proα2(I) chain of type I procollagen
explanation: >-
Radiolabeled collagen analysis in patient fibroblasts establishes loss of the chain.
genes:
- preferred_term: COL1A2
term:
id: hgnc:2198
label: COL1A2
cell_types: *id001
molecular_functions:
- preferred_term: extracellular matrix structural constituent conferring tensile strength
term:
id: GO:0030020
label: extracellular matrix structural constituent conferring tensile strength
modifier: DECREASED
downstream:
- target: Type I collagen homotrimer formation
description: >-
Without proalpha2(I), patient cells assemble alpha1(I) homotrimers.
causal_link_type: DIRECT
gene_products:
- preferred_term: Collagen Alpha-2(I) Chain
term:
id: NCIT:C30015
label: Collagen Alpha-2(I) Chain
modifier: ABSENT
- name: Type I collagen homotrimer formation
biological_scale: MOLECULAR
description: >-
Type I collagen containing three alpha1(I) chains replaces the usual two-alpha1/one-alpha2 heterotrimer.
Patient-fibroblast electrophoresis shows mild overmodification. Homotrimer formation alone does not explain
all differences between cvEDS and COL1A2-related osteogenesis imperfecta.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In P3, proα2(I) and α2(I) chains were absent, and some overmodification due to the formation of proα1(I)
homotrimers was visible as a slight delay in electrophoretic mobility of the α1(I) chains.
explanation: >-
Biochemical demonstration of altered collagen composition in patient cells.
cell_types: *id001
cellular_components:
- preferred_term: collagen type I trimer
term:
id: GO:0005584
label: collagen type I trimer
modifier: ABNORMAL
downstream:
- target: Cardiac valve insufficiency
description: >-
Null-genotype patients develop valve disease; the intermediate tissue-remodeling mechanism is incompletely
resolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Connective tissue mechanical fragility
description: >-
Patient observations link chain loss to skin, joint and procedural tissue fragility without directly
measuring every intermediate.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Cardiac valve insufficiency
biological_scale: ORGANISM
description: >-
Mitral and/or aortic regurgitation can become severe. Mitral prolapse has been documented. Both valves
may be involved, but either can predominate; a fixed mitral-before-aortic sequence is not established.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had a large secundum-type atrial septal defect, mitral valve prolapse with significant mitral regurgitation,
and severe aortic valve regurgitation.
explanation: >-
Direct primary observation of both valve lesions in P3.
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
- preferred_term: aortic valve
term:
id: UBERON:0002137
label: aortic valve
downstream:
- target: Mitral Regurgitation
description: >-
Clinical valve dysfunction includes mitral regurgitation.
causal_link_type: DIRECT
- target: Aortic Regurgitation
description: >-
Clinical valve dysfunction includes aortic regurgitation.
causal_link_type: DIRECT
- target: Left ventricular dilatation
description: >-
Severe valve disease is accompanied by ventricular enlargement; hemodynamic intermediates were not measured.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Connective tissue mechanical fragility
biological_scale: TISSUE
description: >-
Joint laxity, skin hyperextensibility and fragile tissues accompany the collagen defect. Skin electron
microscopy showed altered fibril size and shape in individual patients. Femoral vessel perforation during
catheterization and fatal myocardial disruption during valve surgery demonstrate procedural fragility,
although successful valve replacement is also reported.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Collagen fibrils in skin were slightly larger than normal and more ovoid than in control individuals
explanation: >-
Skin-biopsy ultrastructure in P1; this does not establish valve histopathology.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the femoral artery and vein perforated in the course of preoperative diagnostic cardiac catheterization
explanation: >-
Procedure-associated vascular fragility in P3, not spontaneous arterial rupture.
downstream:
- target: Generalized Joint Hypermobility
description: >-
Lax connective tissues manifest as joint hypermobility.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Skin Hyperextensibility
description: >-
Skin extensibility is a clinical manifestation of altered connective tissue.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Atrophic scars
description: >-
Abnormal wound repair and scar formation accompany tissue fragility.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Bruising susceptibility
description: >-
Easy bruising is documented in the founding cases.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Recurrent shoulder dislocation
description: >-
Joint instability can produce recurrent dislocations.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Tendon rupture
description: >-
Tendon tears are observed in the clinical tissue-fragility phenotype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Muscle tears
description: >-
The founding case links muscle tears to the connective-tissue phenotype; intermediary mechanics were
not measured.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Inguinal hernia
description: >-
Hernias accompany the inherited connective-tissue weakness.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Striae distensae
description: >-
Striae occur in the affected skin; the molecular remodeling steps remain unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Thin skin
description: >-
Thin skin accompanies the connective-tissue defect without a resolved cellular intermediate.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Cardiovascular
name: Mitral Regurgitation
description: >-
Mitral insufficiency can be severe and associated with valve prolapse and chamber enlargement.
phenotype_term:
preferred_term: Mitral regurgitation
term:
id: HP:0001653
label: Mitral regurgitation
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
anterior mitral leaflet prolapse, resulting in severe mitral regurgitation with systolic flow reversal
in the left upper pulmonary vein.
explanation: >-
Direct finding in P1.
- category: Cardiovascular
name: Aortic Regurgitation
description: >-
Aortic insufficiency may occur with mitral disease or as the predominant valve lesion.
phenotype_term:
preferred_term: Aortic regurgitation
term:
id: HP:0001659
label: Aortic regurgitation
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who required aortic valve replacement at age 25 years because of aortic insufficiency.
explanation: >-
The molecularly confirmed brother of P3 had aortic disease requiring replacement.
- category: Musculoskeletal
name: Generalized Joint Hypermobility
description: >-
Hypermobility may be generalized or restricted to peripheral small joints, including a mild childhood presentation.
phenotype_term:
preferred_term: Joint hypermobility
term:
id: HP:0001382
label: Joint hypermobility
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate-severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features."
explanation: >-
Supports the clinical feature; the small, variably ascertained series does not establish a population
frequency.
- reference: PMID:15077201
reference_title: "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects"
explanation: Independently confirms joint hypermobility as a defining feature.
- category: Dermatologic
name: Skin Hyperextensibility
description: >
Hyperextensible skin, one of the three defining features of cvEDS.
phenotype_term:
preferred_term: Hyperextensible skin
term:
id: HP:0000974
label: Hyperextensible skin
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cardiac valvular EDS is mainly characterized by generalized/peripheral joint hypermobility, moderate-severe cardiac valvular disease, skin hyperextensibility and other minor soft tissues features."
explanation: >-
Supports the clinical feature; the small, variably ascertained series does not establish a population
frequency.
- reference: PMID:15077201
reference_title: "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects"
explanation: Independently confirms skin hyperextensibility as a defining feature.
- category: Musculoskeletal
name: Bilateral Flatfoot with Hindfoot Pronation
description: >
Bilateral flatfeet with hindfoot pronation, proposed as a possibly
distinguishing feature of cvEDS within the EDS differential.
phenotype_term:
preferred_term: Pes planus
term:
id: HP:0001763
label: Pes planus
laterality: BILATERAL
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis and hypoplasia of the interphalangeal creases."
explanation: Records bilateral flatfoot as a candidate distinguishing feature of cvEDS.
- name: Mitral valve prolapse
category: Cardiovascular
description: >-
Anterior leaflet prolapse was documented in P1; P3 also had mitral prolapse.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
anterior mitral leaflet prolapse, resulting in severe mitral regurgitation
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Mitral valve prolapse
term:
id: HP:0001634
label: Mitral valve prolapse
- name: Left ventricular dilatation
category: Cardiovascular
description: >-
Left ventricular enlargement accompanied severe valve disease in P1 and P3.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He developed marked left ventricular enlargement and had his aortic and mitral valves replaced with prosthetic
valves
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Left ventricular dilatation
term:
id: HP:4000141
label: Left ventricular dilatation
- name: Left atrial enlargement
category: Cardiovascular
description: >-
Left atrial enlargement was documented in P1 with severe mitral insufficiency.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The left atrium and the left ventricle were dilated
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Left atrial enlargement
term:
id: HP:0031295
label: Left atrial enlargement
- name: Ventricular hypertrophy
category: Cardiovascular
description: >-
Mild ventricular hypertrophy was noted in P1; the source does not specify which ventricle.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
there was mild ventricular hypertrophy, and there was moderate aortic insufficiency.
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Ventricular hypertrophy
term:
id: HP:0001714
label: Ventricular hypertrophy
- name: Atrial fibrillation
category: Cardiovascular
description: >-
Atrial fibrillation preceded valve replacement in P1.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Following episodes of arrhythmias and atrial fibrillation, he underwent mitral and aortic valve replacement
surgery.
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Atrial fibrillation
term:
id: HP:0005110
label: Atrial fibrillation
- name: Secundum atrial septal defect
category: Cardiovascular
description: >-
A large secundum atrial septal defect was described in P3; its frequency and causal connection to COL1A2
deficiency are undetermined.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He had a large secundum-type atrial septal defect, mitral valve prolapse
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Secundum atrial septal defect
term:
id: HP:0001684
label: Secundum atrial septal defect
- name: Atrophic scars
category: Dermatologic
description: >-
Atrophic scars affected the knees and shins in P1 and were also recorded in P2.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
atrophic scars over the knees and shins, easy bruisability
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Atrophic scars
term:
id: HP:0001075
label: Atrophic scars
- name: Thin skin
category: Dermatologic
description: >-
Thin, hyperextensible skin was recorded in P1.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
easy bruisability, and generally hyperextensible and thin skin.
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Thin skin
term:
id: HP:0000963
label: Thin skin
- name: Soft skin
category: Dermatologic
description: >-
Soft skin was reported in P2, P3 and P3's brother, including without substantial hyperextensibility.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
with hyperextensible small joints and soft but not significantly hyperextensible skin
explanation: >-
Primary report, P3's brother.
phenotype_term:
preferred_term: Soft skin
term:
id: HP:0000977
label: Soft skin
- name: Bruising susceptibility
category: Hematologic
description: >-
Easy bruising occurred in the founding adults; it was absent in the 2006 child.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He bruises easily, and his wound healing is delayed.
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Bruising susceptibility
term:
id: HP:0000978
label: Bruising susceptibility
- name: Striae distensae
category: Dermatologic
description: >-
Abdominal striae were documented in P3.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
His skin is soft and hyperextensible, with striae at the lateral aspect of the abdomen.
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Striae distensae
term:
id: HP:0001065
label: Striae distensae
- name: Inguinal hernia
category: Gastrointestinal
description: >-
Bilateral inguinal hernias occurred in P1 and P3, congenital in P3.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He was born with bilateral inguinal hernias
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Inguinal hernia
term:
id: HP:0000023
label: Inguinal hernia
- name: Pectus excavatum
category: Musculoskeletal
description: >-
Pectus excavatum was observed in P1.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
small-joint hypermobility, pectus excavatum, muscle and tendon tears
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Pectus excavatum
term:
id: HP:0000767
label: Pectus excavatum
- name: Recurrent shoulder dislocation
category: Musculoskeletal
description: >-
Recurrent shoulder dislocations began in childhood in P1.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
recurrent shoulder dislocations since childhood, small-joint hypermobility
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Recurrent shoulder dislocation
term:
id: HP:0031610
label: Recurrent shoulder dislocation
- name: Tendon rupture
category: Musculoskeletal
description: >-
Tendon tears were reported in P1, alongside muscle tears.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
pectus excavatum, muscle and tendon tears, bilateral inguinal hernias
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Tendon rupture
term:
id: HP:0100550
label: Tendon rupture
- name: Genu recurvatum
category: Musculoskeletal
description: >-
Bilateral knee hyperextension was described in P3.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He has always had significant large- and small-joint hypermobility, with bilateral genu recurvatum.
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Genu recurvatum
term:
id: HP:0002816
label: Genu recurvatum
- name: Calcaneovalgus deformity
category: Musculoskeletal
description: >-
Pes planus and calcaneovalgus required surgery in P3 during adolescence.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
as a teenager, underwent surgical repair of pes planus and calcaneovalgus.
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Calcaneovalgus deformity
term:
id: HP:0001848
label: Calcaneovalgus deformity
- name: Myopia
category: Ophthalmologic
description: >-
Myopia was reported in P1; no population frequency is established.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He was myopic and had bilateral astigmatism.
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Myopia
term:
id: HP:0000545
label: Myopia
- name: Astigmatism
category: Ophthalmologic
description: >-
Bilateral astigmatism was reported in P1.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He was myopic and had bilateral astigmatism.
explanation: >-
Primary report, P1.
phenotype_term:
preferred_term: Astigmatism
term:
id: HP:0000483
label: Astigmatism
- name: Delayed wound healing
category: Dermatologic
description: >-
Delayed wound healing was reported in P3, but was absent in the child reported in 2006.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He bruises easily, and his wound healing is delayed.
explanation: >-
Primary report, P3.
phenotype_term:
preferred_term: Poor wound healing
term:
id: HP:0001058
label: Poor wound healing
- name: Hallux valgus
category: Musculoskeletal
description: >-
Hallux valgus accompanied severe flatfoot in the six-year-old child.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He presented genua vara recurvata and severe pes planus with valgus heels, hallux valgus, and subluxations
of the toes
explanation: >-
Primary pediatric case.
phenotype_term:
preferred_term: Hallux valgus
term:
id: HP:0001822
label: Hallux valgus
- name: Hypotonia
category: Neurologic
description: >-
Muscle hypotonia with balance problems prompted physiotherapy from infancy in the 2006 child.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He has been receiving physiotherapy since his first year because of equilibrium problems due to muscle
hypotonia and joint hypermobility with deformities of the feet.
explanation: >-
Primary pediatric case.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
- name: Pyloric stenosis
category: Gastrointestinal
description: >-
Hypertrophic pyloric stenosis required surgery in infancy in one child; an isolated observation with uncertain
causal relationship.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
At the age of 2 months he underwent surgery for hypertrophic pyloric stenosis.
explanation: >-
Primary pediatric case.
phenotype_term:
preferred_term: Pyloric stenosis
term:
id: HP:0002021
label: Pyloric stenosis
- name: Arachnodactyly
category: Musculoskeletal
description: >-
Long, thin fingers were reported in the six-year-old child.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
His fingers were long and thin.
explanation: >-
Primary pediatric case.
phenotype_term:
preferred_term: Arachnodactyly
term:
id: HP:0001166
label: Arachnodactyly
- name: Reduced bone density
category: Musculoskeletal
description: >-
Slightly reduced metacarpal cortical width suggested reduced bone density in the 2006 child despite no
fractures; it is not evidence of generalized recurrent-fracture disease.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Bone mineral density was estimated by measuring the cortical width of the left metacarpal phalanges,
and this was slightly diminished, reflecting some decrease in bone mineral density.
explanation: >-
The assessment used cortical width, not DXA.
phenotype_term:
preferred_term: Osteopenia
term:
id: HP:0000938
label: Osteopenia
- name: Lower eyelid ptosis
category: Ophthalmologic
description: >-
Lower eyelid ptosis was proposed as a distinguishing feature in the 2019 report. The source does not establish
upper-eyelid ptosis or ectropion; an exact ontology binding is needed.
evidence:
- reference: PMID:30821104
reference_title: Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis
and hypoplasia of the interphalangeal creases.
explanation: >-
Preserves the reported lower-eyelid feature without converting it to upper-eyelid ptosis.
notes: >-
OLS4 /api/search query: ontology=hp, q='lower eyelid ptosis', rows=15. HP:0000508 Ptosis defines a lowered
upper-eyelid margin; it does not encode the reported lower-eyelid finding.
- name: Hypoplastic interphalangeal creases
category: Musculoskeletal
description: >-
Reduced interphalangeal creases were proposed as a distinguishing feature in the 2019 report; the affected
digits are not specified in the available abstract.
evidence:
- reference: PMID:30821104
reference_title: Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Possibly distinguishing features include bilateral flatfeet with hindfoot pronation, lower eyelid ptosis
and hypoplasia of the interphalangeal creases.
explanation: >-
Retains the observation without inventing digit-specific anatomy.
notes: >-
OLS4 /api/search query: ontology=hp, q='flexion crease', rows=15. Results include HP:0006143 Abnormal finger
flexion crease, absent proximal/distal crease terms and digit-specific effacement terms. The available
source does not specify fingers versus toes or a particular digit, and hypoplasia is not stated to be complete
absence; no narrower anatomy is inferred.
- name: Toe subluxations
category: Musculoskeletal
description: >-
Toe subluxations accompanied flatfoot and hallux valgus in the six-year-old child. An exact toe-joint ontology
binding is needed; finger subluxation is not inferred.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He presented genua vara recurvata and severe pes planus with valgus heels, hallux valgus, and subluxations
of the toes
explanation: >-
Primary pediatric case.
notes: >-
OLS4 /api/search queries: ontology=hp, q='toe dislocation' and q='toe subluxation', rows=15. Results include
HP:0008141 Dislocation of toes and HP:6001403 Hallux sesamoid injury. The source reports subluxation without
a particular toe or joint, so complete dislocation or a sesamoid injury is not asserted.
- name: Muscle tears
category: Musculoskeletal
description: >-
Muscle tears were reported with tendon tears in P1; the involved muscles were not specified. An anatomical
subtype is not inferred.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
pectus excavatum, muscle and tendon tears, bilateral inguinal hernias
explanation: >-
Primary report, P1.
notes: >-
OLS4 /api/search queries: ontology=hp, q='muscle tear' and q='muscle rupture', rows=15. Results include
deltoid, pectoralis major, latissimus dorsi and rotator-cuff lesions, as well as tendon rupture. These
specify structures or tissues that the source's unspecified muscle tears do not identify.
genetic:
- name: COL1A2
notes: >-
COL1A2 encodes the proalpha2(I) chain of type I collagen. cvEDS is associated with biallelic null alleles,
including nonsense c.3601G>T, the exon-7 single-C insertion reported as c.292_293insC in 2006, and splice-altering
variants with cryptic donor use or intron-1 pseudoexon activation. These differ from structural alleles
producing abnormal chains or exon-6-processing defects associated with other collagen disorders. A heterozygous
null allele is not equivalent to a heterozygous structural allele. Legacy variant notation is retained
from the original studies without inventing a transcript accession.
gene_term:
preferred_term: COL1A2
term:
id: hgnc:2198
label: COL1A2
relationship_type: CAUSATIVE
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Cardiac valvular Ehlers-Danlos syndrome (EDS) is a rare EDS subtype, caused by specific recessive variants in the gene encoding pro-α2-chain of type I collagen (COL1A2)."
explanation: Establishes the COL1A2-cvEDS gene-disease relationship and its recessive null-variant specificity.
- reference: PMID:15077201
reference_title: "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Splice site mutations in the COL1A2 gene of type I collagen can give rise to forms of Ehlers-Danlos syndrome (EDS) because of partial or complete skipping of exon 6, as well as to mild, moderate, or lethal forms of osteogenesis imperfecta as a consequence of skipping of other exons."
explanation: >
Documents the allelic series at COL1A2, in which different variant classes
produce EDS subtypes versus osteogenesis imperfecta.
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Heterozygous mutations in the COL1A1 or COL1A2 gene encoding the alpha1 and alpha2 chain of type I collagen generally cause either osteogenesis imperfecta or the arthrochalasis form of Ehlers-Danlos syndrome (EDS)."
explanation: Contrasts the heterozygous COL1A2 disease outcomes with the biallelic-null cvEDS genotype.
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The resulting frameshift introduces a premature termination codon (PTC) in the next amino acid position.
explanation: >-
Sequencing identified a homozygous one-base insertion in exon 7, reported in the preceding sentence as
c.292_293insC.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
In P2, one allele harbored an A→G transition in intron 1 (IVS1+717A→G) that activated a cryptic exon
and led to inclusion of a 105-nt exon that contained four in-frame PTCs.
explanation: >-
Patient-cell sequence analysis identifies cryptic-exon inclusion.
diagnosis:
- name: Molecular Genetic Testing of COL1A2
description: >-
Confirm biallelic COL1A2 variants with a null effect in the appropriate clinical setting. Sequencing or
a suitable gene panel should include deletion/duplication assessment; negative routine sequencing does
not exclude deep intronic variation. Variant class, phase and functional consequences distinguish cvEDS
from other COL1A2 disorders.
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2."
explanation: Molecular confirmation by identification of the biallelic COL1A2 null genotype.
- reference: PMID:15077201
reference_title: "Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "in two of them, COL1A2 messenger RNA (mRNA) instability results from compound heterozygosity for splice site mutations in the COL1A2 gene, and, in the third, it results from homozygosity for a nonsense codon"
explanation: Documents the two molecular genotype configurations that establish the diagnosis.
- reference: PMID:39629471
reference_title: Genetic diagnosis of the Ehlers-Danlos syndromes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic investigations in individuals with an EDS phenotype and severe cardiac valvular disease should
entail thorough evaluation of the COL1A2 gene, including large deletion analysis.
explanation: >-
Contemporary molecular diagnostic guidance.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
CNV detection strategy to identify large deletions or duplications.
explanation: >-
The 2017 classification recommends copy-number analysis when sequencing is unrevealing.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
absence of confirmatory genetic findings does not exclude the diagnosis, as specific types of mutations
(e.g., deep intronic mutations) may go undetected by stan- dard diagnostic molecular techniques.
explanation: >-
Routine molecular methods can miss deep intronic alleles.
- name: Echocardiography
description: >-
Echocardiography assesses valve function and aortic root size at diagnosis or by age five. The 2017 rare-type
review recommends yearly studies even when the initial examination is normal. Pediatric mitral bulging
and later severe regurgitation motivate continuing surveillance.
evidence:
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "careful cardiac follow up with ultrasonography is highly recommended because of the risk for cardiac valvular problems in adulthood"
explanation: Establishes cardiac ultrasonography as the modality for detecting and monitoring the valve lesion.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Measurement of aortic root size and assessment of heart valves by echocar- diogram at the time of diagnosis
or by age 5 years
explanation: >-
The cvEDS management section specifies the baseline timing.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Y early echocardiogram, even if the initial echocardiogram is normal
explanation: >-
The cvEDS-specific management section recommends yearly echocardiography even after a normal initial
examination.
- name: Skin Fibroblast Collagen Electrophoresis
description: >
SDS-polyacrylamide gel electrophoresis of collagens extracted from cultured
skin fibroblasts detects the complete absence of proα2(I) chains, and can
identify affected individuals before or alongside molecular testing.
evidence:
- reference: PMID:16816023
reference_title: "Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Biochemical analysis of collagens extracted from skin fibroblasts is a powerful tool to detect the subset of patients with complete absence of proalpha2(I) collagen chains"
explanation: Establishes fibroblast collagen biochemistry as a diagnostic modality for cvEDS.
- name: Clinical suspicion under the 2017 classification
description: >-
The 2017 criteria suggest cvEDS when severe progressive valve disease and a compatible recessive family
history accompany either another major criterion (skin involvement or joint hypermobility) or at least
two minor criteria (inguinal hernia, pectus deformity, dislocations, foot deformities). Molecular confirmation
is required; these suspicion criteria can miss young children before valve disease is apparent.
evidence:
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Severe progressive cardiac-valvular problems (aortic valve, mitral valve)
explanation: >-
The first major criterion specifies the severe progressive valve phenotype.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
AND a family history compatible with autosomal recessive transmission. Confirmatory molecular testing
is obligatory to reach a final diagnosis.
explanation: >-
The remainder of the criteria specifies recessive inheritance, accompanying criteria and molecular confirmation.
- name: Bone density assessment
description: >-
Consider bone densitometry as recommended in the 2017 cvEDS management review, particularly when clinical
findings raise concern about bone health.
evidence:
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cardiac valve replacement surgery – Consider bone densitometry evaluation
explanation: >-
The cvEDS management list includes consideration of bone densitometry.
treatments:
- name: Cardiac valve replacement
description: >-
Mitral and/or aortic valve replacement has treated severe regurgitation in reported adults. P2 and P3 had
largely uneventful or uncomplicated postoperative courses, whereas P1 died following annular dehiscence
and myocardial disintegration. Procedural planning must account for tissue fragility; these few cases do
not provide an operative-risk rate.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: cardiac valve replacement
term:
id: NCIT:C99546
label: Cardiac Valve Procedure
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Mitral valve replacement surgery was performed, and the postoperative course was largely uneventful.
explanation: >-
Outcome in P2.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He developed marked left ventricular enlargement and had his aortic and mitral valves replaced with prosthetic
valves, with no surgical complications.
explanation: >-
Successful double-valve replacement in P3.
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
there was massive leakage through the left ventricular myocardium with disintegration of the entire left
ventricle, from which the patient died.
explanation: >-
Fatal operative tissue failure in P1; not a general outcome estimate.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
reference_title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cardiac valve replacement surgery – Consider bone densitometry evaluation
explanation: >-
The cvEDS management list explicitly includes valve replacement.
quote_role: REVIEW_SYNTHESIS
target_mechanisms:
- target: Cardiac valve insufficiency
- name: Genetic Counseling
description: >-
Counseling addresses autosomal recessive inheritance, familial testing and the distinction from dominant
structural COL1A2 disorders. When both parents are heterozygous carriers of causative alleles, standard
Mendelian segregation gives a one-in-four chance of an affected child in each pregnancy; this is a conditional
calculation, not a measured recurrence rate in the small published series.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Genetic Counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:30821104
reference_title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Here, we describe two additional affected sisters, who share the homozygous c.3601G>T nonsense variant in COL1A2."
explanation: >
An affected sibling pair sharing a homozygous variant illustrates the
recessive recurrence risk that drives counseling and sibling testing.
- name: Physiotherapy for hypotonia and joint instability
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physiotherapy for hypotonia and joint instability
term:
id: NCIT:C15302
label: Physical Therapy
description: >-
Physiotherapy was provided from infancy for balance problems associated with hypotonia and joint hypermobility
in the 2006 child. This is reported supportive care, with no comparative efficacy estimate.
evidence:
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
reference_title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
He has been receiving physiotherapy since his first year because of equilibrium problems due to muscle
hypotonia and joint hypermobility with deformities of the feet.
explanation: >-
Patient-specific supportive intervention.
discussions:
- discussion_id: cveds_valve_specific_mechanism_gap
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Which effects of alpha1(I) homotrimeric collagen drive progressive valve disease in COL1A2-null patients,
and why is bone fragility usually limited?
attaches_to:
- pathophysiology#Type I collagen homotrimer formation
- pathophysiology#Cardiac valve insufficiency
rationale: >-
Patient observations establish severe valve disease despite relatively limited fracture susceptibility.
The Col1a2-null versus oim mouse comparison shows that homotrimer formation alone does not reproduce the
oim brittle-bone phenotype. It constrains the mechanism but does not explain valve-specific remodeling
or prove an unfolded-protein-response mechanism for cvEDS. Slightly reduced bone density in a child also
argues against treating bone as universally unaffected.
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
These findings suggest that the α2(I) chain is important for functions in soft tissues but that bone
can form in a normal or near-normal fashion in individuals whose cells make no α2(I) chains.
explanation: >-
The founding authors distinguish soft-tissue disease from preserved bone formation.
- reference: PMID:36106514
reference_title: Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Unlike oim homozygotes, we observed no fractures in Col1a2 null homozygotes.
explanation: >-
Animal comparison narrows the proposed mechanism without resolving human valve disease.
proposed_experiments:
- experiment_id: cveds_valve_histopathology_series
name: Histopathology of explanted cvEDS valve tissue
description: >-
Collect and characterize valve tissue explanted at surgery from
molecularly confirmed cvEDS patients, comparing collagen fibril
ultrastructure and matrix composition with valves from non-cvEDS
degenerative valve disease.
- experiment_id: cveds_homotrimer_biomechanics
name: Comparative biomechanics of alpha1(I) homotrimeric collagen
description: >-
Compare homotrimeric and heterotrimeric collagen matrices under controlled cyclic loads and in valve-cell
systems, testing whether altered fatigue behavior or matrix turnover explains progressive valve dysfunction.
This is a proposed experiment, not an established explanation.
notes: >-
cvEDS denotes the biallelic COL1A2-null connective tissue phenotype. It should not be conflated with COL3A1-related
vascular EDS, FLNA-related valvular dystrophy, arthrochalasia EDS, or structural COL1A1/COL1A2 osteogenesis
imperfecta solely because valve disease is present. Reduced fracture susceptibility does not imply normal
bone density in every patient. The 2021 Hyperdynamic Valve case was labeled cvEDS by its authors but did
not report the exact COL1A2 variant, zygosity or collagen studies; it is retained as a clinical lead without
using its generic EDS mortality figures or arterial-risk statements as cvEDS-specific estimates. The small
historical series do not establish population phenotype frequencies or a universal order of valve involvement.
experimental_models:
- name: Patient dermal fibroblast collagen and RNA assays
experimental_model_type: PRIMARY_CELL_CULTURE
cell_source: Skin biopsies from affected individuals
cell_types: *id001
publication: PMID:15077201
description: >-
Cultured dermal fibroblasts were used for radiolabeled collagen electrophoresis, sequencing of splice products,
cDNA mixing and actinomycin-D splicing-order experiments. They demonstrate molecular consequences in skin
cells, rather than valve-specific biomechanics.
modeled_mechanisms:
- target: COL1A2 transcript depletion
relationship: MEASURES
- target: Loss of proalpha2(I) collagen chains
relationship: MEASURES
- target: Type I collagen homotrimer formation
relationship: MEASURES
evidence:
- reference: PMID:15077201
reference_title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Dermal fibroblasts were obtained from explants of skin biopsies from the three individuals.
explanation: >-
Patient-derived primary cultures.
animal_models:
- name: Col1a2-null mouse
species: Mus musculus
genotype: Col1a2tm1b(EUCOMM)Wtsi homozygous null
background: C57BL/6N
publication: PMID:36106514
description: >-
The knockout model lacks alpha2(I) chains and forms homotrimeric type I collagen. Unlike the oim structural-mutant
comparator, it did not show spontaneous fractures; most measured bone properties were preserved, with some
sex- and age-dependent differences. Male null animals developed swollen joints and age-related deterioration.
The study did not establish a specific human valve-remodeling mechanism.
modeled_mechanisms:
- target: Type I collagen homotrimer formation
relationship: RECAPITULATES
fidelity: MODERATE
limitations: >-
A null model distinguishes chain absence from an abnormal oim chain. Its bone and survival findings do
not quantify human valve penetrance or surgical risk.
evidence:
- reference: PMID:36106514
reference_title: Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Unlike oim homozygotes, we observed no fractures in Col1a2 null homozygotes.
explanation: >-
Direct comparison of the null and structural-mutant models.
- reference: PMID:36106514
reference_title: Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Col1a2 null homozygotes did not display bone fragility, but swollen joints were identified in males,
which also displayed age-related deterioration in condition.
explanation: >-
Sex-specific joint and condition findings in the knockout model.
references:
- reference: PMID:15077201
title: Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway.
- reference: PMID:16816023
title: Total absence of the alpha2(I) chain of collagen type I causes a rare form of Ehlers-Danlos syndrome with hypermobility and propensity to cardiac valvular problems.
- reference: PMID:30821104
title: Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2.
- reference: PMID:34434473
title: "Hyperdynamic Valve: A Rare Case of Ehlers-Danlos Syndrome."
- reference: PMID:36106514
title: Collagen (I) homotrimer potentiates the osteogenesis imperfecta (oim) mutant allele and reduces survival in male mice.
- reference: PMID:39629471
title: Genetic diagnosis of the Ehlers-Danlos syndromes.
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf
title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/03/Brady_et_al-2017-American_Journal_of_Medical_Genetics_Part_C-_Seminars_in_Medical_Genetics.pdf"
- reference: url:https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf
title: "https://www.ehlers-danlos.com/wp-content/uploads/2022/12/Malfait_et_al-2017-American_Journal_of_Medical_Genetics_Part_C__Seminars_in_Medical_Genetics.pdf"
- reference: url:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2564565/
title: Total absence of the α2(I) chain of collagen type I causes a rare form of Ehlers‐Danlos syndrome with hypermobility and propensity to cardiac valvular problems - PMC