Abstract 12066: TIMP3 and CHADL Mutations Are Common in Turner Syndrome Aortopathy

Abstract

Introduction: Turner syndrome (TS) is caused by the loss of the second sex chromosome, which occurs in approximately 1 in 2,000 female births. TS alone is an independent risk factor for aortic enlargement. 25 to 50% of those with TS also have a bicuspid aortic valve (BAV) which is present in most who have aortic dissection and rupture. Methods: We used whole exome sequencing to study the genes of 188 TS subjects with BAV (88 cases) or normal aortic valves (100 controls). Aorta diameters as markers of aortopathy severity converted into Z-scores were utilized as covariates with BAV status, and as a sole predictor of genetic variation. Enlarged aorta was defined as an ascending aorta Z-score > 2. Statistical analyses employed a kernel gene-based method, SKAT-O. Results: TS girls and women with BAV had significantly higher ascending aortic Z-scores than those without BAV (1.95 ± 1.97 vs 0.55 ± 1.01, t-test p= 1.6 x 10 -5 ).Mutations in TIMP3 and CHADL achieved exome-wide significance for association with BAV/aortic dilatation (p=1.6x10 -6 and 1.1x10 -6 , respectively). TIMP3 significance increased when aortic root Z-scores were included as a continuous covariant with BAV status (p=2.3x10 -7 ). Overall, 30.7% of those with aortic dilatation had mutations predicted by CADD scores to be deleterious in TIMP3 (8 individuals), CHADL (4 individuals), or both (4 individuals). Those with mutations in both genes were more likely to have enlarged aortas than those with 1 or none (chi-squared p=2.8x10 -3 ). Discussion and conclusions: BAV is known to be associated with aortopathy in TS. We found that TIMP3 and CHADL mutations occur commonly with those findings . TIMP3 is an inhibitor of several aortic matrix metalloproteinases, a group of peptidases that degrade extracellular matrix (ECM). CHADL is a collagen binding protein that regulates collagen fiber formation. Collagens are necessary for aortic structural integrity. We hypothesize that mutations in TIMP3 and CHADL disrupt the critical balance between ECM creation and degradation, thereby compromising aortic strength. There appears to be a synergy between TIMP3 and CHADL functions that may be involved in both BAV development and aortopathy. Both TIMP3 and CHADL may serve as biomarkers and pharmacologic targets for aortic disease in TS.