Cardiac valvular Ehlers-Danlos syndrome (cvEDS) is an ultra-rare autosomal recessive connective-tissue disorder caused by biallelic null variants in COL1A2 that abolish production of the proα2(I) chain of type I collagen. Splice-site variants drive use of cryptic donor sites, creating a downstream premature termination codon and extremely unstable mRNA; homozygous nonsense variants act the same way. Nonsense-mediated decay of COL1A2 mRNA leaves no proα2(I) protein, so type I collagen is assembled as an α1(I) homotrimer rather than the normal heterotrimer. The clinical consequence is distinctive: generalized joint hypermobility and skin hyperextensibility with moderate-to-severe, progressive cardiac valve disease that affects the mitral valve first, and — critically — without the bone fragility that biallelic COL1A2 variants cause in recessive osteogenesis imperfecta. Because the valve disease often becomes apparent only in adolescence or adulthood while the childhood picture can resemble mild hypermobile EDS, lifelong echocardiographic surveillance is the central management issue.
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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 caused by biallelic null variants in
COL1A2 that abolish production of the proα2(I) chain of type I collagen.
Splice-site variants drive use of cryptic donor sites, creating a downstream
premature termination codon and extremely unstable mRNA; homozygous nonsense
variants act the same way. Nonsense-mediated decay of COL1A2 mRNA leaves no
proα2(I) protein, so type I collagen is assembled as an α1(I) homotrimer
rather than the normal heterotrimer. The clinical consequence is distinctive:
generalized joint hypermobility and skin hyperextensibility with
moderate-to-severe, progressive cardiac valve disease that affects the mitral
valve first, and — critically — without the bone fragility that biallelic
COL1A2 variants cause in recessive osteogenesis imperfecta. Because the valve
disease often becomes apparent only in adolescence or adulthood while the
childhood picture can resemble mild hypermobile EDS, lifelong
echocardiographic surveillance is the central management issue.
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
references:
- reference: PMID:30821104
title: "Cardiac valvular Ehlers-Danlos syndrome is a well-defined condition due to recessive null variants in COL1A2."
findings:
- statement: >
cvEDS is a recognizable EDS subtype defined by recessive COL1A2 null
variants, with progressive heart valve disease affecting the mitral valve
first.
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: "Clinical data and literature review allowed to better define the clinical spectrum of cardiac valvular EDS which now emerges as a more recognizable EDS variant with progressive heart valve disease firstly affecting the mitral valve."
explanation: Establishes cvEDS as a well-defined entity with a characteristic valve-involvement sequence.
- statement: >
Absence of bone fragility separates cvEDS from recessive osteogenesis
imperfecta caused by COL1A2 variants.
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: "The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2"
explanation: Records the key differential-diagnostic boundary against COL1A2-related osteogenesis imperfecta.
- 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."
findings:
- statement: >
Complete absence of proα2(I) chains produces cardiac valvular disease
without bone involvement.
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 complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement."
explanation: The founding mechanistic observation defining the cvEDS phenotype-genotype relationship.
- reference: PMID:28306229
title: "The 2017 international classification of the Ehlers-Danlos syndromes."
findings:
- statement: >
cvEDS is one of the 13 EDS subtypes recognized by the 2017 International
EDS Classification.
evidence:
- reference: PMID:28306229
reference_title: "The 2017 international classification of the Ehlers-Danlos syndromes."
supports: SUPPORT
evidence_source: OTHER
snippet: "The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes."
explanation: Anchors cvEDS in the current EDS nosology.
inheritance:
- name: Autosomal recessive inheritance
description: >
cvEDS is autosomal recessive, requiring biallelic COL1A2 null variants —
either homozygous nonsense variants or compound heterozygous splice-site
variants. Heterozygous carriers do not have the disorder.
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.
prevalence:
- population: Worldwide reported cases
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >
Only five molecularly confirmed patients had been reported as of the 2019
review, plus the two affected sisters described in that report. Population
prevalence has not been estimated.
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: Cumulative published case count for molecularly confirmed cvEDS.
- 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: >
In childhood the presentation can be indistinguishable from mild hypermobile
EDS — joint hypermobility and skin hyperextensibility without recognizable
valve disease — which is why the diagnosis is often not suspected at this
stage.
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.
- phase: Progressive valvular disease
age_range: Adolescence to adulthood
notes: >
Heart valve disease is progressive and affects the mitral valve first, with
aortic involvement following; it reaches moderate-to-severe degree and
constitutes the prognostically dominant manifestation, which is why lifelong
echocardiographic surveillance is recommended.
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: Establishes the progressive, mitral-first course of the valve disease.
- 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.
pathophysiology:
- name: COL1A2 Null Allele and Nonsense-Mediated mRNA Decay
biological_scale: MOLECULAR
description: >
Biallelic COL1A2 null variants destabilize the transcript. Splice-site
variants lead to use of cryptic splice donor sites, creating a downstream
premature termination codon and extremely unstable mRNA; homozygous nonsense
codons act directly. Either route engages the nonsense-mediated RNA decay
pathway, so essentially no COL1A2 message survives to be translated. The
order in which neighboring introns are removed is an important determinant
of whether a given splice-site variant produces exon skipping or this
decay-activating outcome.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: nonsense-mediated mRNA decay
modifier: INCREASED
term:
id: GO:0000184
label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
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 splice site mutations led to use of cryptic splice donor sites, creation of a downstream premature termination codon, and extremely unstable mRNA."
explanation: Describes the molecular route from splice-site variant to transcript destruction.
- 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 order of intron removal is an important variable in prediction of mutation outcome at splice sites"
explanation: Explains why some COL1A2 splice variants give cvEDS-type null alleles rather than in-frame exon skipping.
downstream:
- target: Complete Absence of proalpha2(I) Collagen Chains
description: >
Destruction of COL1A2 mRNA by nonsense-mediated decay removes the template
for the proα2(I) chain, so no proα2(I) protein is made.
causal_link_type: DIRECT
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 complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement."
explanation: Links transcript loss to complete absence of the chain and to the resulting phenotype.
- name: Complete Absence of proalpha2(I) Collagen Chains
biological_scale: MOLECULAR
description: >
Type I collagen is normally a heterotrimer of two proα1(I) chains and one
proα2(I) chain. With no proα2(I) available, the molecule is assembled
instead as an α1(I) homotrimer. This altered composition is detectable by
SDS-PAGE analysis of collagens extracted from cultured skin fibroblasts,
which remains a practical way to identify affected individuals.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
cellular_components:
- preferred_term: collagen type I trimer
modifier: ABNORMAL
term:
id: GO:0005584
label: collagen type I trimer
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
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: "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: Establishes complete proα2(I) deficiency as the defining molecular lesion.
- 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: Documents the fibroblast biochemical assay that demonstrates the missing chain.
downstream:
- target: Progressive Cardiac Valve Matrix Failure
description: >
Type I collagen lacking its α2(I) chain cannot maintain normal valve
extracellular matrix, and valve leaflet competence degrades over time.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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 complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement."
explanation: >
Directly links the absent chain to valvular disease; the intermediate
steps in valve matrix remodeling are not resolved in the literature,
hence an indirect causal link.
- target: Generalized Soft Tissue Laxity Without Bone Fragility
description: >
The same collagen defect produces joint hypermobility and skin
hyperextensibility, but characteristically spares bone strength.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
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: Records the soft-tissue arm of the phenotype alongside the cardiac arm.
- name: Progressive Cardiac Valve Matrix Failure
biological_scale: TISSUE
description: >
Valve leaflet extracellular matrix, which depends on normal type I collagen,
degenerates progressively. The mitral valve is affected first, with the
aortic valve involved later, producing moderate-to-severe valvular
insufficiency. Because valve disease can emerge well after the soft-tissue
features, it may not be apparent in childhood.
cell_types:
- preferred_term: valve interstitial cell
term:
id: CL:4030032
label: valve interstitial cell
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
- preferred_term: aortic valve
term:
id: UBERON:0002137
label: aortic valve
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: Establishes progressive valve disease with mitral-first involvement.
- 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: Documents the delayed, adult-onset expression of the valve phenotype.
downstream:
- target: Cardiac Valvular Insufficiency and Heart Failure Risk
description: >
Progressive leaflet failure produces mitral and/or aortic regurgitation of
moderate to severe degree, ultimately requiring surgical valve repair or
replacement.
causal_link_type: DIRECT
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: "moderate-severe cardiac valvular disease"
explanation: Records the clinical severity of the valvular endpoint.
- name: Cardiac Valvular Insufficiency and Heart Failure Risk
biological_scale: ORGANISM
description: >
Moderate-to-severe mitral and/or aortic regurgitation is the defining and
prognostically dominant manifestation of cvEDS, and the reason lifelong
echocardiographic surveillance and eventual valve surgery are the core of
management.
locations:
- preferred_term: mitral valve
term:
id: UBERON:0002135
label: mitral valve
- preferred_term: aortic valve
term:
id: UBERON:0002137
label: aortic valve
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: "characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects"
explanation: Cardiac valvular defects are one of the three defining features of the syndrome.
- 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: Frames adult valvular disease as the principal prognostic risk requiring surveillance.
- name: Generalized Soft Tissue Laxity Without Bone Fragility
biological_scale: ORGANISM
description: >
Generalized or peripheral joint hypermobility with skin hyperextensibility,
soft skin, atrophic scarring, and easy bruising. Bone fragility is
characteristically absent — the feature that separates cvEDS from the
recessive osteogenesis imperfecta also caused by biallelic COL1A2 variants,
and from dominant osteogenesis imperfecta with severe valve disease. In
childhood this arm can resemble mild hypermobile EDS, which is why the
diagnosis is often not suspected until valve disease appears.
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
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: "The absence of bone fragility in our patients indicates that cardiac valvular EDS is also separated from patients with autosomal recessive osteogenesis imperfecta and variants in COL1A2, as well as from individuals with autosomal dominant osteogenesis imperfecta and severe cardiac valvular disease."
explanation: States the absence of bone fragility and its differential-diagnostic significance.
- 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 presentation that precedes recognizable valve disease.
phenotypes:
- category: Cardiovascular
name: Mitral Regurgitation
description: >
Mitral valve insufficiency, the first and most consistently affected valve
in cvEDS, progressing to moderate or severe degree.
phenotype_term:
preferred_term: Mitral regurgitation
term:
id: HP:0001653
label: Mitral regurgitation
clinical_course: PROGRESSIVE
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: >
Supports the disease-phenotype association and the mitral-first sequence.
No frequency band is assigned: the source describes the order in which
valves are affected, not the proportion of patients affected, and with
only a handful of reported patients no frequency estimate is defensible.
- category: Cardiovascular
name: Aortic Regurgitation
description: >
Aortic valve insufficiency, typically following mitral involvement as part
of the progressive valvular disease.
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: "characterized by joint hypermobility, skin hyperextensibility, and cardiac valvular defects"
explanation: >
Supports cardiac valvular defects as a defining feature; the abstract does
not name the aortic valve specifically, so support for aortic involvement
in particular is partial. The MONDO definition of this disorder specifies
mitral and/or aortic valve insufficiency.
- category: Musculoskeletal
name: Generalized Joint Hypermobility
description: >
Generalized or peripheral joint hypermobility, one of the three defining
features of cvEDS and typically the earliest to be noticed.
phenotype_term:
preferred_term: Joint hypermobility
term:
id: HP:0001382
label: Joint hypermobility
frequency: VERY_FREQUENT
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: >
Snippet supports the disease-phenotype association. The VERY_FREQUENT band
is a clinical estimate, not a reported statistic: the author wording
"mainly characterized by" maps to VERY_FREQUENT under the dismech
qualitative mapping (docs/frequency-evidence-guidelines.md, Pattern C).
With only a handful of reported patients, no cohort percentage exists.
- 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
frequency: VERY_FREQUENT
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: >
Snippet supports the disease-phenotype association. The VERY_FREQUENT band
is a clinical estimate, not a reported statistic: the author wording
"mainly characterized by" maps to VERY_FREQUENT under the dismech
qualitative mapping (docs/frequency-evidence-guidelines.md, Pattern C).
With only a handful of reported patients, no cohort percentage exists.
- 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
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.
genetic:
- name: COL1A2
notes: >
Encodes the proα2(I) chain of type I collagen. cvEDS is caused specifically
by biallelic null variants — compound heterozygous splice-site variants that
activate nonsense-mediated decay, or homozygous nonsense variants such as
c.3601G>T. This is a distinct genotype class from the COL1A2 variants that
cause osteogenesis imperfecta or arthrochalasia EDS: the same gene produces
a different disease depending on whether the allele is null (cvEDS) or
structurally dominant-negative. Heterozygous COL1A2 variants generally cause
osteogenesis imperfecta or arthrochalasia-type EDS rather than cvEDS.
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.
diagnosis:
- name: Molecular Genetic Testing of COL1A2
description: >
The modern confirmatory test. Diagnosis requires demonstrating biallelic
COL1A2 null variants — compound heterozygous splice-site variants that
activate nonsense-mediated decay, or homozygous nonsense variants such as
c.3601G>T. Identifying the variant class matters diagnostically as well as
mechanistically, because heterozygous structural COL1A2 variants cause
osteogenesis imperfecta or arthrochalasia EDS rather than cvEDS.
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.
- name: Echocardiography
description: >
Transthoracic echocardiography both establishes the valvular lesion and
forms the basis of lifelong surveillance, since valve disease may not become
apparent until adulthood.
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.
- 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.
treatments:
- name: Echocardiographic Surveillance
description: >
Lifelong cardiac follow-up with ultrasonography is strongly recommended
because valvular problems may not appear until adulthood, long after the
joint and skin features are evident. This is the central management
intervention in cvEDS.
therapeutic_modality: OTHER
treatment_term:
preferred_term: Supportive Care
term:
id: NCIT:C15747
label: Supportive Care
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: Direct recommendation for echocardiographic surveillance in patients lacking proα2(I) chains.
- name: Cardiac Valve Repair or Replacement
description: >
Surgical repair or replacement of the mitral and/or aortic valve for
moderate-to-severe valvular insufficiency, the definitive treatment for the
prognostically dominant manifestation.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: Cardiac Valve Procedure
term:
id: NCIT:C99546
label: Cardiac Valve Procedure
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: "moderate-severe cardiac valvular disease"
explanation: >
Establishes the severity of valve disease that constitutes the surgical
indication. The cited abstract characterizes the lesion rather than
reporting surgical outcomes, so support for the intervention itself is
partial; cvEDS-specific valve-surgery outcome data are not available in
the current evidence base.
- name: Genetic Counseling
description: >
Autosomal recessive counseling with 25% sibling recurrence risk. Affected
sibling pairs are documented, so testing of siblings of a proband is
particularly relevant.
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.
discussions:
- discussion_id: cveds_valve_specific_mechanism_gap
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does complete loss of the proα2(I) collagen chain damage cardiac valves
while sparing bone, when the same gene's dominant-negative variants cause
osteogenesis imperfecta?
attaches_to:
- pathophysiology#Progressive Cardiac Valve Matrix Failure
- pathophysiology#Generalized Soft Tissue Laxity Without Bone Fragility
rationale: >-
The founding report described the valve-specific, bone-sparing outcome of
complete proα2(I) absence as "surprising", and the tissue-selectivity has
not since been mechanistically explained. Why an α1(I) homotrimer suffices
for skeletal mineralization but not for long-term valve leaflet integrity is
unresolved, and with only a handful of reported patients there is no
histopathological series of affected valves to work from. This is why the
causal edge from the absent chain to valve matrix failure is curated as
indirect with unknown intermediates.
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 complete absence of pro alpha 2(I) chains has the surprising effect of producing cardiac valvular disease without bone involvement."
explanation: >-
The authors' own framing of the tissue selectivity as surprising is the
evidence that it remains mechanistically unexplained.
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 the tensile and fatigue properties of α1(I) homotrimeric versus
normal heterotrimeric type I collagen matrices under cyclic loading that
mimics valve leaflet motion versus static skeletal loading, to test
whether cyclic-load fatigue explains the valve-selective failure.
notes: >
Curated as a standalone entry rather than as a subtype of the umbrella
Ehlers-Danlos Syndrome entry, following the precedent of Vascular and
Hypermobile Ehlers-Danlos Syndrome, and named as a curation gap in the
Ehlers-Danlos_Syndromes grouping notes and its MONDO mapping-consistency note.
Differential-diagnosis boundary: cvEDS, arthrochalasia EDS, and osteogenesis
imperfecta are all COL1A1/COL1A2 disorders. The discriminator is variant class
and zygosity — biallelic null alleles with complete proα2(I) loss give cvEDS,
whereas heterozygous structural (dominant-negative) variants give osteogenesis
imperfecta or arthrochalasia EDS. The absence of bone fragility is the
clinical corollary and the practical bedside discriminator against recessive
COL1A2 osteogenesis imperfecta.
Sourcing note: no deep-research provider artifact backs this entry. It was
built directly from primary literature located via the PubMed E-utilities API,
with every PMID cached through the reference validator and every snippet
machine-verified as an exact quote. There is also no GeneReviews chapter for
cardiac valvular EDS to serve as a phenotype baseline — a PubMed
`GeneReviews[Book]` search returns eight EDS-related chapters (vascular,
classic, hypermobile, TNXB classical-like, periodontal, PLOD1- and
FKBP14-kyphoscoliotic, musculocontractural) and no cardiac-valvular one, so
the subtype is covered only within broader EDS literature.
Phenotype-coverage note: the phenotype list is deliberately short because the
molecularly confirmed cohort is tiny (seven patients across the two
defining reports). Aortic regurgitation is retained at `supports: PARTIAL`
because no published source names aortic involvement in cvEDS specifically —
a targeted PubMed search returned only classical/hypermobile EDS cardiac
studies — so the claim rests on the generic "cardiac valvular defects"
phrasing plus the MONDO definition, and is marked accordingly rather than
overstated.
No module conformance is declared. The disorder is not an aortopathy
(aortopathy_tgfbeta_dysregulation covers medial degeneration and aortic
dissection, which cvEDS does not feature), and although chronic regurgitant
volume overload could in principle engage
cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling, no cvEDS-specific
evidence for ventricular remodeling or heart failure was found in the current
evidence base, so asserting that conformance would outrun the sources.