Low penetrance COL5A1 variants in a young patient with intracranial aneurysm and very mild signs of Ehlers-Danlos syndrome

Spontaneous cervical artery dissection (CeAD) is a major cause of ischemic stroke in young adults, whose genetic susceptibility factors are still largely unknown. Nevertheless, subtle ultrastructural connective tissue alterations (especially in the collagen fibril morphology) are recognized in a large proportion of CeAD patients, in which recent genetic investigations reported an enrichment of variants in genes associated with known connective tissue disorders. In this regard, COL5A1 variants have been reported in a small subset of CeAD patients, with or without classical Ehlers-Danlos syndrome (cEDS) features. We investigated a 22-year-old patient with intracranial aneurysm and mild connective tissue manifestations reminiscent of EDS. Whole-exome sequencing identified two COL5A1 missense variants in trans configuration: NM_000093.5:c.[1588G>A];[4135C>T], NP_000084.3:p.[(Gly530Ser)];[(Pro1379Ser)]. Functional assays demonstrated a significant decrease of collagen α1(V) chain expression in both heterozygous parents compared to control cells, and an additive effect of these two variants in the proband. Interestingly, both parents manifested very subtle EDS signs, such as atrophic scars, recurrent bone fractures, colonic diverticulosis, varicose veins, and osteoarthritis. Our findings emphasize the involvement of COL5A1 in the predisposition to vascular phenotypes and provide novel insights on the c.1588G>A variant, whose functional significance has not been definitely established. In fact, it was previously reported as both “disease modifying”, and as a biallelic causative mutation (with heterozygous individuals showing subtle clinical signs of cEDS). We speculated that the c.1588G>A variant might lead to overt phenotype in combination with additional genetic “hits” lowering the collagen α1(V) chain expression below a hypothetical disease threshold.