TY - JOUR
T1 - The genetic basis of Turner syndrome aortopathy
AU - Corbitt, Holly
AU - Gutierrez, Jacob
AU - Silberbach, Michael
AU - Maslen, Cheryl L.
N1 - Funding Information:
We would like to thank many Turner syndrome study subjects and their families for their generous donation of time and body to our studies and to the Turner Syndrome Society of the.U.S. for facilitating our interactions with their members over the years. Thanks to Drs. Shaine Morris, Claus Gravholt, Kristian Mortensen, Rebecca Tippner-Hedges, and the GenTAC investigators for their contributions to this work. This work was supported by technical assistance from Jessica Kushner, Brian Booty, Carrie Farrar, Sarah Egan, and Dr. Harry C. Dietz. This work was supported by a grant from OHSU, funds from the Knight Cardiovascular Institute (to CLM), Friends of Doernbecher (to HC), and the Ravelle Research Fund of the Turner Syndrome Society of the U.S. (to MS). The whole exome sequencing was provided through the NHLBI Resequencing and Genotyping Service at the University of Washington (D. Nickerson, director), NHLBI Grant number: 268201100037C-0-0-1.
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
KW - aortic disease
KW - bicuspid aortic valve
KW - congenital cardiovascular disease
KW - polygenic trait
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U2 - 10.1002/ajmg.c.31686
DO - 10.1002/ajmg.c.31686
M3 - Article
C2 - 30770620
AN - SCOPUS:85061572246
VL - 181
SP - 117
EP - 125
JO - American Journal of Medical Genetics - Seminars in Medical Genetics
JF - American Journal of Medical Genetics - Seminars in Medical Genetics
SN - 0148-7299
IS - 1
ER -