LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.

TitleLTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.
Publication TypeJournal Article
Year of Publication2018
AuthorsGuo, D-C, Regalado, ES, Pinard, A, Chen, J, Lee, K, Rigelsky, C, Zilberberg, L, Hostetler, EM, Aldred, M, Wallace, SE, Prakash, SK, Leal, SM, Bamshad, MJ, Nickerson, DA, Natowicz, M, Rifkin, DB, Milewicz, DM
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
JournalAm J Hum Genet
Date Published2018 04 05
KeywordsAdult, Aged, 80 and over, Aneurysm, Dissecting, Animals, Aortic Aneurysm, Thoracic, Blood Pressure, Female, Genetic Predisposition to Disease, Homozygote, Humans, Latent TGF-beta Binding Proteins, Male, Mice, Middle Aged, Mutation, Pedigree

The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs25 and p.Glu750) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities.

Alternate JournalAm. J. Hum. Genet.
PubMed ID29625025
PubMed Central IDPMC5985335
Grant ListHHSN268201100037C / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL062594 / HL / NHLBI NIH HHS / United States
UL1 RR024148 / RR / NCRR NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
P01 HL110869 / HL / NHLBI NIH HHS / United States
R01 HL109942 / HL / NHLBI NIH HHS / United States