| Domain | Curated finding | Evidence level/source year | Ontology/code suggestions |
|---|---|---|---|
| Identity and aliases | Arthrochalasia Ehlers–Danlos syndrome (aEDS); formerly EDS type VIIA for **COL1A1**-related disease and type VIIB for **COL1A2**-related disease; Mendelian, autosomal-dominant heritable connective-tissue disorder (pqac-00000001, pqac-00000004) | International expert classification, 2017 | **MONDO:0007525**; labels: arthrochalasia EDS, EDS VIIA, EDS VIIB |
| Causal gene: COL1A1 | Heterozygous pathogenic variants affecting exon 6 of **COL1A1**, encoding collagen type I α1 chain, cause aEDS; COL1A1-associated disease may be more severe because approximately three quarters of collagen-I molecules can contain an abnormal α1 chain (pqac-00000000, pqac-00000010, pqac-00000019) | Human genetic, biochemical, and ultrastructural evidence; 2008–2022 | **HGNC:2197**; **NCBI Gene:1277**; collagen α1(I) chain |
| Causal gene: COL1A2 | Heterozygous pathogenic variants affecting exon 6 of **COL1A2**, encoding collagen type I α2 chain, cause aEDS; approximately half of collagen-I molecules may contain an abnormal α2 chain (pqac-00000000, pqac-00000019) | Human genetic, biochemical, and ultrastructural evidence; 2008–2024 | **HGNC:2198**; **NCBI Gene:1278**; collagen α2(I) chain |
| Variant spectrum | Lesions are usually splice-donor, splice-acceptor, or genomic variants producing complete or partial exon-6 loss. A demonstrated **COL1A1 IVS5-2A>T** variant activated a cryptic splice site and deleted the first 15 nucleotides of exon 6; variants are germline and may be inherited or de novo (pqac-00000001, pqac-00000018, pqac-00000020) | Molecularly confirmed human cases; 2008–2020 | Sequence Ontology labels: splice-acceptor variant, splice-donor variant, exon loss, in-frame deletion |
| Molecular mechanism | Exon-6 loss removes the type-I-procollagen N-proteinase cleavage site and may remove the N-telopeptide cross-linking lysine and start of the Gly-X-Y triple-helical region. Failed cleavage produces collagen retaining its N-propeptide—**pN-collagen** (pqac-00000018, pqac-00000020, pqac-00000021) | Direct patient-fibroblast biochemical evidence and expert synthesis; 2008–2020 | GO labels: collagen biosynthetic process, collagen fibril organization, extracellular-matrix organization, protein processing |
| Fibrillogenesis | Retained pNα1(I) or pNα2(I) chains disturb collagen fibrillogenesis. Skin electron microscopy shows small, loosely or randomly organized fibrils with irregular or ragged contours; dominant-negative interference is strongly inferred but not directly proven in the cited experiment (pqac-00000018, pqac-00000019) | Human in-vitro biochemical and skin-biopsy TEM evidence; 2008 | **CL:0000057** fibroblast; labels: dermal fibroblast, collagen fibril, dermis, collagen-containing extracellular matrix |
| Hallmark phenotype | Congenital bilateral hip dislocation is the principal hallmark, accompanied by severe generalized joint hypermobility and recurrent dislocations or subluxations. One molecularly proven but unpublished patient reportedly had unilateral hip dislocation (pqac-00000001) | International diagnostic consensus, 2017 | **HP:0001382** joint hypermobility; **HP:0001374** congenital hip dislocation; labels: recurrent joint dislocation, joint subluxation |
| Minor phenotypes | Skin hyperextensibility, hypotonia, kyphoscoliosis, mild osteopenia, tissue fragility, atrophic scars, easy bruising or hematomas, redundant skin, clubfoot, and congenital knee dislocation occur variably (pqac-00000001, pqac-00000014, pqac-00000018) | Consensus criteria and human cases; 2008–2022 | **HP:0000974** hyperextensible skin; **HP:0001252** hypotonia; **HP:0002751** kyphoscoliosis; **HP:0000938** osteopenia; **HP:0001075** atrophic scars; **HP:0000978** bruising susceptibility |
| Epidemiology | Population prevalence and incidence are unknown. The 2022 systematic review identified approximately **42 published patients worldwide**, with substantial uncertainty from underdiagnosis and publication bias (pqac-00000010, pqac-00000011) | PRISMA systematic review, 2022 | **MONDO:0007525**; rare disease; do not apply aggregate EDS prevalence estimates to aEDS |
| Vascular and cardiac risk | A vascular complication was reported in **1/17 aEDS patients (6%)** in a systematic review. Progressive mitral, aortic, and tricuspid regurgitation has also been reported, but estimates rest on very small samples (pqac-00000007, pqac-00000012) | Systematic review and isolated human case; 2018–2022 | Labels: vascular complication, mitral regurgitation, aortic regurgitation, tricuspid regurgitation |
| Diagnosis | Suggestive findings are congenital bilateral hip dislocation plus either skin hyperextensibility or severe generalized joint hypermobility with multiple dislocations or subluxations, together with at least two minor criteria. Definitive diagnosis requires molecular confirmation (pqac-00000001) | International expert classification, 2017 | Sequence **COL1A1** and **COL1A2**; connective-tissue multigene panel; deletion/duplication analysis if sequencing is negative |
| Ancillary diagnostics | Cultured skin-fibroblast collagen analysis can demonstrate abnormal pN-collagen processing. Skin-biopsy transmission electron microscopy may show supportive fibril abnormalities but does not replace molecular confirmation (pqac-00000001, pqac-00000018, pqac-00000019) | Human biochemical/TEM evidence and consensus; 2008–2017 | NCIT labels: skin biopsy, transmission electron microscopy, fibroblast culture, protein electrophoresis |
| Treatment and trials gap | No curative or disease-modifying therapy exists. Care is individualized and multidisciplinary: cautious physiotherapy and strengthening, joint protection, orthoses or mobility aids, pain management, wound precautions, and selective orthopedic intervention. No aEDS-specific treatment-response rates or interventional trials were identified (pqac-00000011, pqac-00000014, pqac-00000024) | Systematic and scoping reviews; 2022–2024 | NCIT labels: physical therapy, occupational therapy, orthotic device, pain management, orthopedic surgery, supportive care, genetic counseling |
| Surgery evidence | EDS-wide 2024 evidence comprised 71 primary orthopedic studies—38 case reports, 14 case series, and 19 retrospective cohorts—with no randomized trials and inconsistent outcomes. Findings were not aEDS-specific (pqac-00000023, pqac-00000024) | Scoping review, October 2024; indirect evidence | NCIT labels: orthopedic surgery, preoperative assessment, postoperative care; annotate as EDS-wide indirect evidence |
| Animal and model gap | No validated naturally occurring animal disease or exact **COL1A1/COL1A2 exon-6 aEDS** model was identified. A combined osteogenesis-imperfecta/EDS mouse is mechanistically adjacent but does not reproduce the defining exon-6 lesion and should not be curated as an aEDS-equivalent model | Targeted literature search through 2024; negative or adjacent evidence | **NCBI Taxon:10090** for the adjacent mouse model only; model status: not disease-equivalent |


*Table: Compact extraction table summarizing the identity, genetics, mechanism, phenotype, epidemiology, diagnosis, management, vascular evidence, and research gaps for arthrochalasia Ehlers–Danlos syndrome.*