Donner I, Sipilä LJ, Plaketti R-M, et al. Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology. Vascular. 2022;30(5):842-847. doi:10.1177/17085381211033157
Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology
|Author:||Donner, Iikki1,2; Sipilä, Lauri J1,2; Plaketti, Roosa-Maria1,2;|
1Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki, Finland
2Genome-Scale Biology Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland
3Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
4PEDEGO Research Unit, Medical Research Center Oulu, Oulu University Hospitaland University of Oulu, Oulu, Finland
5Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
6Department of Vascular Surgery, Oulu University Hospital, Oulu, Finland
7Department of Radiology, Oulu University Hospital, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 0.4 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2023030129078
|Publish Date:|| 2023-03-01
Background: 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.
Methods: 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.
Results: 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 COL4A2, proximal to COL4A1.
Conclusions: As type IV collagens are essential for the stability and integrity of the vascular basement membrane and involved in vascular disease, we conclude that COL4A1 and COL4A2 are strong candidates for VAA susceptibility genes.
|Pages:||842 - 847|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This research was funded by the Academy of Finland (Finnish Center of Excellence Programs 2012–2017, 250345 and 2018–2025, 312041). The research received no other specific grants from any funding agency in the public, commercial, or not-for-profit sectors.
Donner I, Sipilä LJ, Plaketti R-M, et al, Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology, Vascular (vol.30 issue 5) pp. 842-847. Copyright © 2021 The Author(s). DOI:10.1177/17085381211033157.