Supravalvar aortic stenosis (SVAS) is a characteristic feature of Williams-Beuren syndrome (WBS). SVAS is present in 67% of those with WBS, but severity varies; 21% have clinically significant SVAS requiring surgical intervention while 33% have no appreciable aortic disease. Little is known about genetic modifiers outside the 7q11.23 region that might contribute to SVAS severity. To investigate, we collaboratively phenotyped 473 individuals with WBS and performed the largest whole-genome-sequencing study to date. We developed a set of strategies for modifier discovery including extreme phenotyping (surgical SVAS vs. no SVAS) and prioritization of non-synonymous variants with increased predicted functional impact along with an allele frequency difference between the extreme phenotype groups. We identified pathways enriched in common or less frequent variants, followed by association testing of SVAS severity with the enriched pathways. The common variant analysis identified pathways including the extracellular matrix and the innate immune system, while pathways encompassing adaptive immunity, ciliary function, lipid metabolism and PI3KAKT were captured by both the common and less frequent variant analyses. Cell cycle and estrogen responsive pathways were among those identified through the less frequent variant analysis. Among the 69 genes reported in other large genome wide association studies assessing aortic traits, 11 genes, including PCSK9 and ILR6, were found in our study, suggesting overlapping disease mechanisms. In summary, this study presents novel strategies for identification of disease modifiers in rare conditions like WBS.
Williams‐Beuren syndrome is considered to be at increased risk for celiac disease, as for recent literature data and celiac disease guidelines, despite pathogenic mechanisms are still unclear. Our study analyzed the prevalence of autoimmune disorders, HLA DQ2 and/or DQ8 haplotypes, of transglutaminase antibodies and of diagnosis of celiac disease in a cohort of 93 Williams‐Beuren syndrome's patients (mean age 21.26 years). Our study showed an increased prevalence of celiac disease equal to 10.8% (10/93 patients). We did not find a significant different frequency of predisposing HLA in subjects with Williams‐Beuren syndrome compared to literature data in the general population (49.5% vs. 42.9%, with p > .1), nor a susceptibility to autoimmunity. This suggests that the increased prevalence of celiac disease in Williams‐Beuren syndrome cannot be ascribed to HLA haplotype and may be related to other factors that still need to be identified in these patients.
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