The genetic basis of Turner syndrome aortopathy

Abstract

Our goal is to identify the genetic underpinnings of bicuspid aortic valve and aortopathy in Turner syndrome. We performed whole exome sequencing on 188 Turner syndrome study subjects from the GenTAC registry. A gene-based burden test, SKAT-O, was used to evaluate the data using bicuspid aortic valve (BAV) and aortic dimension z-scores as covariates. This revealed that TIMP3 was associated with BAV and increased aortic dimensions at exome-wide significance. It had been previously shown that genes on chromosome Xp contribute to aortopathy when hemizygous. Our analysis of Xp genes revealed that hemizygosity for TIMP1, a functionally redundant paralogue of TIMP3, increased the odds of having BAV aortopathy compared to individuals with more than one TIMP1 copy. The combinatorial effect of a single copy of TIMP1 and TIMP3 risk alleles synergistically increased the risk for BAV aortopathy to nearly 13-fold. TIMP1 and TIMP3 are tissue inhibitors of matrix metalloproteinases (TIMPs) which are involved in development of the aortic valve and protection from thoracic aneurysms. We propose that the combination of TIMP1 haploinsufficiency and deleterious variants in TIMP3 significantly increases the risk of BAV aortopathy in Turner syndrome, and suggest that TIMP1 hemizygosity may play a role in euploid male aortic disease.

Heart and Turner syndrome

“…This delayed diagnosis is probably related to the fact that cardiac echography may be difficult to perform in young children. The prevalence of BAV in TS is much higher than in the general population, where it is present in 2-3% in males and in 0.05% in females [13]. BAV is a predisposing factor for subsequent aortic dilatation and even aortic dissection [2].…”

“…Histology from TS patients showed collagen fibrosis with activation of connective tissue production. Immunochemistry showed an excessive TGFβ signaling and activation of the downstream SMAD signaling [13]. High TGFβ activity increases fibrosis and inflammation, and induces the release of metalloproteases and may eventually lead to AD and dissection.…”

Prevalence and progression of aortic dilatation in adult patients with Turner syndrome: a cohort study

“…The most frequent one is bicuspid aortic valve (BAV), occurring in 20% to 30% of TS (3). In the general population, its prevalence is 2-3% in males and 0.05% in females (4). It has been reported that the prevalence of BAV and other congenital cardiovascular malformations are more frequent in patients with a homogenous 45,X karyotype than in patients with 45,X/46,XX mosaicism (1,5).…”

Congenital heart defects associated with aneuploidy syndromes: New insights into familiar associations

“…The products of these genes are members of the tissue inhibitor of matrix metalloproteinase family, known inhibitors of matrix metalloproteinases which themselves degrade the extracellular matrix. Their findings show a 20‐fold risk of having a BAV in the setting of only having one copy of TIMP1 (i.e., Turner syndrome) and a specific variant of TIMP3 (Corbitt et al, ; Corbitt, Gutierrez, Silberbach, & Maslen, ).…”