Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p><em>Background:</em> Visceral artery aneurysms (VAAs) can be fatal if ruptured. Although a relatively rare incident, it holds a contemporary mortality rate of approximately 12%. VAAs have multiple possible causes, one of which is genetic predisposition. Here, we present a striking family with seven individuals affected by VAAs, and one individual affected by a visceral artery pseudoaneurysm.</p><p><em>Methods:</em> We exome sequenced the affected family members and the parents of the proband to find a possible underlying genetic defect. As exome sequencing did not reveal any feasible protein-coding variants, we combined whole-genome sequencing of two individuals with linkage analysis to find a plausible non-coding culprit variant. Variants were ranked by the deep learning framework DeepSEA.</p><p><em>Results:</em> Two of seven top-ranking variants, NC_000013.11:g.108154659C>T and NC_000013.11:g.110409638C>T, were found in all VAA-affected individuals, but not in the individual affected by the pseudoaneurysm. The second variant is in a candidate cis-regulatory element in the fourth intron of <em>COL4A2</em>, proximal to <em>COL4A1</em>.</p><p><em>Conclusions:</em> As type IV collagens are essential for the stability and integrity of the vascular basement membrane and involved in vascular disease, we conclude that <em>COL4A1</em> and <em>COL4A2</em> are strong candidates for VAA susceptibility genes.</p></div>