To characterize genetic variation that impacts the severity of blood vessel disease in patients with elastin insufficiency and Williams syndrome, we are using a combination of approaches. First, using a technique called quantitative train locus analysis, we identified different regions of the mouse genome where differences in genetic background impact the degree of hypertension and vascular narrowing in Eln+/- mice. Subsequent work has identified distinct genetic modifiers from under two of those peaks (Ren1 and Ncf1, manuscripts covering these data are in preparation) with additional genomic regions under continued investigation. With the identification of these modifiers, further study into the mechanism of action and potential therapeutic value can be undertaken. Secondly, we have acquired tissue samples from individuals with WS that have severe arteriopathy and from those with more mild cardiovascular features. By growing those tissues and studying the differences between the two groups (gene expression, rate of proliferation, etc), genes and pathways can be identified that differentiate the two. Such work can be done in the fibroblasts themselves or by turning the cells into smooth muscle cells by the production of induced pluripotent stem cells (IPSC). To date, we have generated multiple IPSC lines and are working to derive smooth muscle cells that deposit elastin. Finally, we plan to look for association of rare and common genomic variants with disease severity in WS patients. Toward this end, we have collected questionnaire data, medical records and DNA on more than 150 individuals with Williams Beuren syndrome. WBS deletion size was determined for each subject. We next plan to sequence the DNA of each individual with a typical deletion and compare genetic variants between those with mild cardiovascular disease and those with a severe phenotype. To optimize power, we will focus our analysis on candidate genes and pathways identified from information in the literature or from our animal and cell studies. Taken together, these three complimentary projects will allow us to identify genes and pathways important for altering the severity of cardiovascular disease in patients with WS.
| Kopp, Nathan D; Parrish, Phoebe C R; Lugo, Michael et al. (2018) Exome sequencing of 85 Williams-Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior. Mol Genet Genomic Med 6:749-765 |
| Duque Lasio, Maria Laura; Kozel, Beth A (2018) Elastin-driven genetic diseases. Matrix Biol : |
| Baldridge, Dustin; Heeley, Jennifer; Vineyard, Marisa et al. (2017) The Exome Clinic and the role of medical genetics expertise in the interpretation of exome sequencing results. Genet Med 19:1040-1048 |
