LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan.

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LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections Dong-chuan Guo, Ellen S. Regalado, Amelie Pinard, Jiyuan Chen, Kwanghyuk Lee, Christina Rigelsky, Lior Zilberberg, Ellen M. Hostetler, Micheala Aldred, Stephanie E. Wallace, Siddharth K. Prakash, Suzanne M. Leal, Michael J. Bamshad, Deborah A. Nickerson, Marvin Natowicz, Daniel B. Rifkin, Dianna M. Milewicz The American Journal of Human Genetics Volume 102, Issue 4, Pages 706-712 (April 2018) DOI: 10.1016/j.ajhg.2018.03.002 Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of Homozygous LTBP3 Mutations in HTAD (A) Pedigrees of families showing segregation of LTBP3 variants with DASS and aortic disease. The age at diagnosis (dx) or death (d) in years is shown below the individual symbols. The legend shows the symbols representing the phenotypic features in the family members. (B) A coronal computed tomography angiogram (CTA) of the neck and chest illustrates innominate artery aneurysm (star), aortic arch aneurysm with stent (arrowhead), and pronounced tortuosity of the left internal carotid artery (rectangle) in individual III:2 of family TAA376. (C) Schematic diagram of the LTBP-3 domain structure and mutation. The pathogenic variants associated with HTAD are shown in red letters above the protein diagram, and the rare variants identified in cases with early-onset thoracic aortic dissection are shown in black letters below the protein diagram. The American Journal of Human Genetics 2018 102, 706-712DOI: (10.1016/j.ajhg.2018.03.002) Copyright © 2018 American Society of Human Genetics Terms and Conditions

Figure 2 Ltbp3−/− Mice Have Decreased Blood Pressure and Altered Aortic Pathology, Which Lead to Thoracic Aortic Dilatation (A and B) The average number of elastic lamellae in mouse aortic walls was increased in Ltbp3−/− mice (n = 3) compared to wild-type mice (n = 4). (C) Average systolic, diastolic, and mean blood pressures in wild-type (n = 6) and Ltbp3−/− (n = 5) mice. Data are presented as the mean ± SD for each mouse genotype. (D) Average diameters of the aortic root and ascending aorta were measured by echocardiogram of 2-month-old wild-type (n = 8), Ltbp3−/− (n = 5), Fbn1mgR/mgR (n = 9), and Fbn1mgR/mgR/Ltbp3−/− (n = 5) mice; values were normalized to the weight of each mouse. Data are presented as the mean ± SD for each mouse genotype. ∗p < 0.05, ∗∗p < 0.005. The American Journal of Human Genetics 2018 102, 706-712DOI: (10.1016/j.ajhg.2018.03.002) Copyright © 2018 American Society of Human Genetics Terms and Conditions