Classical Ehlers‐Danlos syndrome with a propensity to arterial events: A new report on a French family with a COL1A1 p.(Arg312Cys) variant

Abstract

Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of connective tissue disorders. Overlapping features including arterial aneurysms/dissections in both classical and vascular EDS are a major challenge in the clinical diagnosis of these subtypes. The COL1A1 p.(Arg312Cys) variant leads to a phenotype of classical EDS with a propensity to arterial complications. Our report describes a twogeneration family with one individual presenting with a dissection of the right external iliac artery. The primary suspicion of vascular EDS with the unsatisfactory identification of a COL3A1 benign variant was secondarily readjusted with the identification of COL1A1 p.(Arg312Cys) variant. This raises the question of the association of COL1A1 p.(Arg312Cys) with arterial complications and the need for a gene panel including not only the usual genes tested in search of classical or vascular EDS but also COL1A1.

Multisystemic manifestations in a cohort of 75 classical Ehlers-Danlos syndrome patients: natural history and nosological perspectives

“…However, an exact estimation of prevalence and risk of these vascular complaints and possible genotype-phenotype correlations in cEDS are still missing [ 16 , 119 ]. In particular, either the specific c.934C > T, p.(Arg312Cys) variant in COL1A1 or COL5A1 variants causing glycine substitutions at the C-terminal end of the triple helix domain have been associated with propensity to severe arterial events in early adulthood, but these assumptions are still a matter of debate due to the limited number of reports [ 10 – 14 , 22 , 25 ]. In our cEDS cohort, easy bruising, which is present to a variable degree in all EDS subtypes, was the most common finding (~ 87%).…”

“…The classical (cEDS), vascular (vEDS), and the molecularly unsolved hypermobile (hEDS) EDS subtypes account for more than 90% of patients. cEDS (MIM #130000) has an estimated prevalence of 1/20,000 and it is principally caused by heterozygous pathogenic variants in COL5A1 or COL5A2 encoding type V collagen and rarely by the c.934C > T p.(Arg312Cys) missense variant in COL1A1 encoding type I collagen [1][2][3][4][5][6][7][8][9][10][11][12][13][14].…”

“…In particular, it is reported that cEDS patients may show delayed motor development with mild hypotonia, characteristic facial features, fatigue and muscle cramps, premature rupture of fetal membranes, cervical insufficiency during pregnancy, rectal prolapse in early childhood, mild scoliosis, and cardiac/blood vessel fragility including mitral/tricuspid valve prolapse, and aortic root dilatation. In very rare individuals, especially (but not exclusively) in those with the COL1A1 p.(Arg312Cys) missense variant, spontaneous rupture of large arteries, intracranial aneurysms, and arteriovenous fistulae may occur [ 5 – 7 , 9 – 14 , 18 – 26 ].…”

A novel COL1A1 variant in a family with clinical features of hypermobile Ehlers‐Danlos syndrome that proved to be a COL1‐related overlap disorder

“…It is associated with potential vascular fragility, ranging from the absence of vascular complication to arterial ruptures in cEDS-affected patients. 9,10,12,13 Interestingly, cardiovascular explorations of our patients showed no major vascular complication except a small thoracic aorta dilatation in patient II.3, but which could also be a ductus diverticulum or a post-traumatic aortic pseudoaneurysm since the patient had a car accident in the past. An annual vascular follow-up will be organized to monitor the evolution of this abnormality.…”

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

“…A specific arginine to cysteine substitution in proα1(I)‐collagen ( COL1A1 , c.934C>T, p.(Arg312Cys)) was first described in two children with cEDS features (Nuytinck et al, 2000). Subsequently, 15 additional individuals harboring this substitution were reported (Adham et al, 2019; Colombi et al, 2017; Duong et al, 2019; Gaines et al, 2015; Malfait et al, 2007; Ritelli et al, 2013), some of whom presented arterial ruptures (Adham et al, 2019; Gaines et al, 2015; Malfait et al, 2007). Biallelic pathogenic TNXB variants are associated with classical‐like EDS type 1 (clEDS1, MIM #606408), hitherto reported in 51 individuals, with clinical features resembling cEDS except for the absence of atrophic scarring (Burch et al, 1997; Green et al, 2020; Schalkwijk et al, 2001).…”