Figure 1.

Identification of TGFB2 as the causative gene responsible for thoracic aortic disease in families TAA288 and MS239. (a) Pedigrees of family TAA288 and MS239 with the legend indicating the disease and mutation status of the family members. The age at diagnosis of aortic root enlargement and/or dissection (“dx”) is shown in years and “d” indicates age at death. A single asterisk indicates individuals whose DNA was used in genome-wide mapping. DNA from the circled individuals was used for exome sequencing. (b) Parametric two-point and multi-point LOD score profile for thoracic aortic aneurysms and dissections (TAAD) across the human genome in family TAA288 based on the Affymetrix 50K GeneChips Hind array data. The parametric two-point (grey) and multi-point (red) LOD scores are on the y-axis and are correlated to physical location of human chromosome on the x-axis. (c) Parametric two-point LOD score profile for TAAD across the human genome in family MS239. (d) Schematic representation of the TGFB2 gene and the protein domains and preproprotein proteolytic processing sites for mature TGF-β2. Boxes represent exons 1-7 with the untranslated regions (UTRs) and the open reading frame designated. The domains of the protein are designated using orange, blue and pink. The proteolytic sites of TGF-β2 preproprotein are marked with scissors symbol. Proteolytic cleavage sites remove the signal peptides from the amino-terminus and release the mature TGF-β2 from the latent associated peptide. The TGFB2 mutations identified in this study are indicated in pink type. Below the gene diagram are the rare variants found in the NHLBI exome sequencing variant server (http://evs.gs.washington.edu/EVS/); blue type designates variants predicted to be possibly or probably damaging by PolyPhen-2 analysis and black type designates variants predicted to be benign.