Next-generation sequencing in a large pedigree segregating visceral artery aneurysms suggests potential role of COL4A1/COL4A2 in disease etiology
| Autor: | Riku Katainen, Roosa-Maria Plaketti, Juho Kariniemi, Outi Kuismin, Pekka Romsi, Linda M. Forsström, Mervi Aavikko, Anna Kuosmanen, Iikki Donner, Lauri A. Aaltonen, Lauri J. Sipilä |
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| Přispěvatelé: | Organismal and Evolutionary Biology Research Programme, Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Research Programs Unit, Doctoral Programme in Integrative Life Science, Helsinki Institute of Life Science HiLIFE, Lauri Antti Aaltonen / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Institute for Molecular Medicine Finland |
| Rok vydání: | 2021 |
| Předmět: |
Collagen Type IV
0301 basic medicine Marfan syndrome medicine.medical_specialty Visceral artery COL4A1 COL4A2 030204 cardiovascular system & hematology DNA sequencing MECHANISMS 03 medical and health sciences 0302 clinical medicine Aneurysm MISSENSE MUTATION Internal medicine medicine Genetic predisposition Humans HETEROGENEITY Radiology Nuclear Medicine and imaging BRAIN STABILITY IDENTIFICATION business.industry Mortality rate High-Throughput Nucleotide Sequencing Arteries General Medicine COL4A2 MUTATIONS medicine.disease GENE MARFAN-SYNDROME Disease etiology Pedigree 030104 developmental biology IV 3121 General medicine internal medicine and other clinical medicine non-coding variants Cardiology next-generation sequencing Surgery Cardiology and Cardiovascular Medicine business Aneurysm False genetic susceptibility |
| Zdroj: | Vascular. 30:842-847 |
| ISSN: | 1708-539X 1708-5381 1081-5465 |
| DOI: | 10.1177/17085381211033157 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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