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Turner syndrome is caused by complete or partial loss of the second sex chromosome, occurring in ~1 in 2,000 female births. There is a greatly increased incidence of aortopathy of unknown etiology, including bicuspid aortic valve (BAV), thoracic aortic aneurysms, aortic dissection and rupture. We performed whole exome sequencing on 188 Turner syndrome participants from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Related Conditions (GenTAC). A gene-based burden test, the optimal sequence kernel association test (SKAT-O), was used to evaluate the data with BAV and aortic dimension z-scores as covariates. Genes on chromosome Xp were analyzed for the potential to contribute to aortopathy when hemizygous. Exome analysis revealed that  TIMP3  was associated with indices of aortopathy at exome-wide significance (p = 2.27 x 10 −7 ), which was replicated in a separate cohort. The analysis of Xp genes revealed that  TIMP1 , which is a functionally redundant paralogue of  TIMP3 , was hemizygous in >50% of our discovery cohort and that having only one copy of  TIMP1  increased the odds of having aortopathy (OR = 9.76, 95% CI = 1.91–178.80, p = 0.029). The combinatorial effect of a single copy of  TIMP1  and  TIMP3  risk alleles further increased the risk for aortopathy (OR = 12.86, 95% CI = 2.57–99.39, p = 0.004). The products of genes encoding tissue inhibitors of matrix metalloproteinases (TIMPs) are involved in development of the aortic valve and protect tissue integrity of the aorta. We propose that the combination of X chromosome  TIMP1  hemizygosity and variants of its autosomal paralogue  TIMP3 , significantly increases the risk of aortopathy in Turner syndrome.

TIMP3 and TIMP1 are risk genes for bicuspid aortic valve and aortopathy in Turner syndrome