Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers–Danlos syndrome

Abstract

Classical Ehlers–Danlos syndrome (cEDS) is a heritable connective tissue disorder mainly caused by pathogenic variants in COL5A1 or COL5A2, encoding type V collagen. Its diagnosis, based on clinical criteria and molecular confirmation, can be challenging. We report the molecular and clinical characteristics of 168 probands (72 clinically evaluated at our center) and 65 relatives with a clinical presentation of cEDS. Type V collagen defects were found in 145 probands, 121 (83.5%) were located in COL5A1 and 24 (16.5%) in COL5A2. Although 85.6% of molecularly confirmed patients presented the two major clinical criteria (generalized joint hypermobility, hyperextensible skin with atrophic scarring), significant inter‐ and intrafamilial phenotypic variability was noted. COL5A2 variants often caused a more severe phenotype. Vascular complications were rare in individuals with type V collagen defects (1.4%). Among the 72 probands clinically evaluated in our center, the mutation detection rate was 82.0%. The majority (68.1%) harbored COL5A1/COL5A2 defects. Yet, 13.9% harbored a defect in another gene (COL1A1, PLOD1, TNXB, AEBP1) highlighting important clinical overlap and the need for molecular confirmation of the diagnosis as this has implications regarding follow‐up and genetic counseling. Eighteen percent of the 72 probands remained molecularly unexplained and a COL5A1 variant of unknown significance was identified in 6.9%.

Animal Models of Ehlers–Danlos Syndromes: Phenotype, Pathogenesis, and Translational Potential

“…The heart was morphologically normal, but immunohistochemical analysis revealed increased deposition of type I and III collagen in mitral and aortic valves and ventricular myocardium, supposedly as a compensatory mechanism for disturbed fibrillogenesis due to reduced type V collagen content (Lincoln et al, 2006). Although these findings indicate the importance of type V collagen in vascular and cardiac structure, integrity and/or function, cardiovalvular problems are rarely of clinical significance and severe or life-threatening arterial manifestations are only sporadically observed in cEDS patients (Bowen et al, 2017;Malfait, 2018;Angwin et al, 2020;Colman et al, 2021).…”

“…It is inherited in an autosomal dominant fashion and about 90% of cEDS patients harbor a heterozygous mutation in either the COL5A1 or COL5A2 gene, encoding the pro-α1- and pro-α2-chain of type V collagen, respectively. The majority of these mutations result in a non-functional COL5A1 allele and give rise to COL5A1 haploinsufficiency with reduced type V collagen protein levels, while mutations in COL5A1 or COL5A2 that lead to a structural defect (e.g., glycine substitution or in-frame exon skip) have a dominant negative effect ( Symoens et al, 2012 ; Colman et al, 2021 ). The most common isoform of type V collagen is the [α1(V)] 2 α2(V) heterotrimer found in skin, tendon, ligaments, cornea, and bone, where it forms heterotypic fibrils with type I collagen.…”

Gonosomal Mosaicism for a Novel COL5A1 Pathogenic Variant in Classic Ehlers-Danlos Syndrome

“…COL5A1 variants are scattered throughout the gene, and the majority of them lead to COL5A1 haploinsufficiency, usually resulting from nonsense-mediated mRNA decay (NMD) [ 4 , 5 , 6 ]. Variants located at the signal peptide or C-propeptide of proα1(V) reduce type V procollagen secretion, and this corroborates the hypothesis that “functional” type V collagen haploinsufficiency is a crucial factor in cEDS pathogenesis.…”

“…Many cEDS individuals carry a heterozygous pathogenic or likely pathogenic variant in either the COL5A1 or COL5A2 genes, which encode for the type V collagen alpha 1 (α-1) and α-2 polypeptide chains, respectively [ 4 , 5 , 6 ]. Type V collagen occurs as heterotrimers of three different polypeptide chains: alpha (α)-1, α-2 and α-3, of which the different α-chains are encoded by COL5A1, COL5A2 and COL5A3 [ 7 ] or two copies of alpha-1 and one copy of alpha-2; it also occurs as a homotrimer of α-1 polypeptides.…”

Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports

“…This helical domain is flanked by globular amino-(N) and carboxy-(C) terminal domains, called propeptides, which are cleaved off by ADAMTS2 and bone morphogenic protein/mammalian tolloid metalloproteinase (BMP-1/mTLD), respectively, resulting in the formation of a mature collagen molecule that can then assemble into highly ordered cross-striated fibrils and fibres (7). cEDS is hallmarked by generalised joint hypermobility, skin hyperextensibility and fragility with delayed wound healing and formation of atrophic scars, easy bruising, and other signs of connective tissue fragility (Table I), but with extensive inter-and intrafamilial variability (8). It is mainly caused by pathogenic variants in COL5A1 that introduce a premature termination codon and lead to nonsense-mediated decay of the mutant allele, resulting in a reduced amount of type V collagen in the ECM.…”