Journal
CIRCULATION-GENOMIC AND PRECISION MEDICINE
Volume 12, Issue 4, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGEN.118.002437
Keywords
cohort studies; coronary artery disease; DNA; genetics; humans; integrins; talin
Funding
- SCAD Research, Inc
- Ann and George M. Fisher Endowed Research Fund
- Mayo Clinic Center for Individualized Medicine
- Chicago Mercantile Exchange Foundation
- SCAD Research Australia
- Kristin Schmidtfrerick memorial fund
- Mayo Clinic Departments of Cardiovascular Medicine, Internal Medicine, and Molecular Pharmacology and Experimental Therapeutics
- National Institutes of Health Building Interdisciplinary Research Careers in Women's Health Program [NH HD 65987]
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BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an uncommon idiopathic disorder predominantly affecting young, otherwise healthy women. Rare familial cases reveal a genetic predisposition to disease. The aim of this study was to identify a novel susceptibility gene for SCAD. METHODS: Whole-exome sequencing was performed in a family comprised of 3 affected individuals and filtered to identify rare, predicted deleterious, segregating variants. Immunohistochemical staining was used to evaluate protein expression of the identified candidate gene. The prevalence and spectrum of rare (< 0.1%) variants within binding domains was determined by next-generation sequencing or denaturing highperformance liquid chromatography in a sporadic SCAD cohort of 675 unrelated individuals. RESULTS: We identified a rare heterozygous missense variant within a highly conserved beta-integrin-binding domain of TLN1 segregating with familial SCAD. TLN1 encodes talin 1-a large cytoplasmic protein of the integrin adhesion complex that links the actin cytoskeleton and extracellular matrix. Consistent with high mRNA expression in arterial tissues, robust immunohistochemical staining of talin 1 was demonstrated in coronary arteries. Nine additional rare heterozygous missense variants in TLN1 were identified in 10 sporadic cases. Incomplete penetrance, suggesting genetic or environmental modifiers of this episodic disorder, was evident in the familial case and 5 individuals with sporadic SCAD from whom parental DNA was available. CONCLUSIONS: Our findings reveal TLN1 as a disease-associated gene in familial and sporadic SCAD and, together with abnormal vascular phenotypes reported in animal models of talin 1 disruption, implicate impaired structural integrity of the coronary artery cytoskeleton in SCAD susceptibility.
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