Dataset Information

A novel mutation in COL3A1 associates to vascular Ehlers-Danlos syndrome with predominant musculoskeletal involvement.

ABSTRACT:

Background

Vascular Ehlers-Danlos syndrome (vEDS) is a heritable connective tissue disorder caused by defects in the type III collagen protein. It is generally considered the most severe form of Ehlers-Danlos syndrome (EDS) due to an increased risk of spontaneous artery or organ rupture. vEDS has an extremely heterogeneous presentation and muscle rupture is considered a minor diagnostic criterium.

Methods

A patient with a long history of inconclusive examinations and investigations was referred to our unit. The clinical picture was mainly characterized by muscle ruptures, whereas the cardiovascular involvement was limited to mitral regurgitation. We performed a panel analysis of genes associated with inheritable heart diseases using the TruSight Cardio kit (Illumina). A skin biopsy was then performed for functional studies to analyze the different forms of collagen molecules produced in vitro by cutaneous fibroblasts.

Results

The patient presented the novel variant c.3478A>G (p.Ile1160Val) in COL3A1 (NM_000090.3), whose pathogenicity was supported by biochemical analysis of type III collagen.

Conclusion

In this report, we describe a case of vEDS with predominant and severe musculoskeletal involvement. Our findings provide insight into genetic variants and clinical expression of vEDS, broadening the clinical scenario of the syndrome.

SUBMITTER: Ruscitti F

PROVIDER: S-EPMC8457703 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The management of arterial pathology in individuals with vascular Ehlers-Danlos syndrome (vEDS) remains a challenge. Here we describe the correlation between COL3A1 gene mutation type and the clinical phenotype in individuals with vEDS.Individuals with confirmed molecular diagnoses of vEDS were enrolled in a multi-institutional natural history study. Data collected included demographics, clinical and family histories, arterial pathology (aneurysm, dissection, and rupture), operative details, and autopsy reports. Individuals were classified into two cohorts by the type of COL3A1 mutations and their effect on the amount of normal collagen produced: those with mutations that lead to minimal (MIN) production (10%-15%) of normal type III collagen and those with haploinsufficiency (HI) mutations that lead to production of 50% of the normal type III collagen.A cohort of 68 individuals (72%) from 56 families had arterial pathology (44% male) with 13% HI. The HI group was older at the time of their first vascular event (mean, 42 [range, 26-58] years vs 33 [range, 8-62] years; P = .016) and had a higher incidence of aortic pathology than the MIN group (56% vs 21%; P = .025). Visceral arterial pathology was seen in 43 arteries in 23 individuals in the MIN group vs only one artery in five individuals in the HI group. Emergency surgical procedures were more likely to be undertaken when vEDS diagnosis was not known (81% vs 41%; P = .005), and 81% of these procedures were open surgical repair compared with 19% endovascular repairs (P = .019). Open and endovascular repairs were equally used in the elective setting. Postoperative complications were highest when the diagnosis of vEDS was not known (62% vs 14%; P < .001) and when procedures were undertaken in an emergency setting (5% vs 55% P < .001). Mortality due to arterial complications was 0% in the HI cohort and 21% in the MIN cohort (P = .132).Arterial pathology in vEDS individuals is related to the underlying COL3A1 mutation type. The arterial pathology in individuals with HI mutations occurs at later ages with a higher incidence of aortic disease compared with other COL3A1 mutation types. Molecular diagnosis is recommended because diagnosis confirmation, appropriate surveillance, and prophylactic interventions in an elective setting improve surgical outcomes.