TY - JOUR
T1 - Identification of Rare Genetic Variants in Familial Spontaneous Coronary Artery Dissection and Evidence for Shared Biological Pathways
AU - Turley, Tamiel N.
AU - Theis, Jeanne L.
AU - Evans, Jared M.
AU - Fogarty, Zachary C.
AU - Gulati, Rajiv
AU - Hayes, Sharonne N.
AU - Tweet, Marysia S.
AU - Olson, Timothy M.
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/9
Y1 - 2023/9
N2 - 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.
AB - 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.
KW - acute coronary syndrome
KW - co-segregation analysis
KW - collagen genes
KW - myocardial infarction
KW - spontaneous coronary artery dissection
KW - whole-genome sequencing
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U2 - 10.3390/jcdd10090393
DO - 10.3390/jcdd10090393
M3 - Article
AN - SCOPUS:85172084122
SN - 2308-3425
VL - 10
JO - Journal of Cardiovascular Development and Disease
JF - Journal of Cardiovascular Development and Disease
IS - 9
M1 - 393
ER -