Identification of Rare Genetic Variants in Familial Spontaneous Coronary Artery Dissection and Evidence for Shared Biological Pathways

被引:1
|
作者
Turley, Tamiel N. [1 ,2 ]
Theis, Jeanne L. [2 ]
Evans, Jared M. [3 ]
Fogarty, Zachary C. [3 ]
Gulati, Rajiv [4 ]
Hayes, Sharonne N. [4 ]
Tweet, Marysia S. [4 ]
Olson, Timothy M. [2 ,4 ,5 ]
机构
[1] Mayo Clin, Grad Sch Biomed Sci, Mol Pharmacol & Expt Therapeut Track, Rochester, MN 55905 USA
[2] Mayo Clin, Cardiovasc Genet Res Lab, Rochester, MN 55905 USA
[3] Mayo Clin, Dept Quantitat Hlth Sci, Div Computat Biol, Rochester, MN 55905 USA
[4] Mayo Clin, Dept Cardiovasc Med, Rochester, MN 55905 USA
[5] Mayo Clin, Dept Pediat & Adolescent Med, Div Pediat Cardiol, Rochester, MN 55905 USA
关键词
acute coronary syndrome; collagen genes; co-segregation analysis; spontaneous coronary artery dissection; myocardial infarction; whole-genome sequencing; ENDOTHELIAL-CELLS; ADHERENS JUNCTIONS; R-CADHERIN; MUSCLE; MUTATIONS; ASSOCIATION; ADHESION; IQGAP1; COLLAGENS; INTEGRINS;
D O I
10.3390/jcdd10090393
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Rare familial spontaneous coronary artery dissection (SCAD) kindreds implicate genetic disease predisposition and provide a unique opportunity for candidate gene discovery. Whole-genome sequencing was performed in fifteen probands with non-syndromic SCAD who had a relative with SCAD, eight of whom had a second relative with extra-coronary arteriopathy. Co-segregating variants and associated genes were prioritized by quantitative variant, gene, and disease-level metrics. Curated public databases were queried for functional relationships among encoded proteins. Fifty-four heterozygous coding variants in thirteen families co-segregated with disease and fulfilled primary filters of rarity, gene variation constraint, and predicted-deleterious protein effect. Secondary filters yielded 11 prioritized candidate genes in 12 families, with high arterial tissue expression (n = 7), high-confidence protein-level interactions with genes associated with SCAD previously (n = 10), and/or previous associations with connective tissue disorders and aortopathies (n = 3) or other vascular phenotypes in mice or humans (n = 11). High-confidence associations were identified among 10 familial SCAD candidate-gene-encoded proteins. A collagen-encoding gene was identified in five families, two with distinct variants in COL4A2. Familial SCAD is genetically heterogeneous, yet perturbations of extracellular matrix, cytoskeletal, and cell-cell adhesion proteins implicate common disease-susceptibility pathways. Incomplete penetrance and variable expression suggest genetic or environmental modifiers.
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页数:22
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