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.

自发性颈动脉夹层（CeAD）是年轻人缺血性中风的主要原因，其遗传易感性因素仍是未知之数。然而，在大部分CeAD患者中都发现了微妙的超微结构结缔组织改变（尤其是在胶原纤维形态上），其中最近的遗传研究报道了与已知结缔组织疾病有关的基因中的变体丰富。在这方面，已经报道了一小部分CeAD患者的COL5A1变体，无论是否患有经典的Ehlers-Danlos综合征（cEDS）特征。

我们调查了22岁的颅内动脉瘤和轻度结缔组织表现，令人联想到EDS的患者。全外显子组测序鉴定出两个反式配置的COL5A1错义变体：NM_000093.5：c。[1588G> A]; [4135C> T]，NP_000084.3：p。[（Gly530Ser）]; [（Pro1379Ser）]。功能分析表明，与对照细胞相比，两个杂合体亲本中的胶原α1（V）链表达均显着降低，并且这两个变异体在先证者中具有累加作用。有趣的是，父母双方都表现出非常微妙的EDS征象，例如萎缩性疤痕，复发性骨折，结肠憩室病，静脉曲张和骨关节炎。

我们的发现强调了COL5A1参与血管表型的易感性，并为c.1588G> A变体提供了新颖的见解，其功能性意义尚未明确。实际上，先前报道它既是“疾病修饰”又是双等位基因致病突变（杂合子个体表现出微弱的cEDS临床症状）。我们推测c.1588G> A变异可能会导致明显的表型，再加上其他遗传“击中”，从而将胶原α1（V）链表达降低到假设疾病阈值以下。