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Activity Number: 339 - Individual Treatment Rule and Precision Medicine
Type: Contributed
Date/Time: Wednesday, August 5, 2020 : 10:00 AM to 2:00 PM
Sponsor: Biometrics Section
Abstract #313500
Title: Finding Genetic Modifiers Associating with Vascular Disease Severity in Williams Beuren Syndrome
Author(s): Delong Liu* and Phoebe Parrish and Charles Billington and Russell Knutsen and Beth Kozel
Companies: National Institutes of Health and National Institutes of Health and National Institutes of Health and National Institutes of Health and National Institutes of Health
Keywords: geneset association test; Williams Beuren syndrome ; rare disease

Williams Beuren syndrome (WBS) occurs in 1:10000 individuals. It is characterized by hemi-deletion of 1.5-1.8 mega bases on chromosome 7q11.23. Phenotype varies among affected individuals with 20-30 percent of WBS patients having severe supravalvar aortic stenosis (SVAS) requiring surgical intervention, and others with mild or no clear vascular phenotype. The large variability suggests that other genetic factors may contribute to the degree of stenosis severity. We studied a cohort of 104 WBS patients on whom whole exome sequencing had been undertaken, aiming at finding association of genetic modifiers with SVAS phenotypes. We performed geneset-based association test with 3 steps: pre-screening variants with marginal allele frequency and CADD score for the patients with severe SVAS (n=16) and no SVAS (n=46); assigning the selected variants to biological pathways; and then running SKAT-O and Wald-statistics based association tests of the pathways with the phenotypes of the 62 WBS. We identified 4 pathways relevant to SVAS pathophysiology and validated the findings in animal models. We will discuss geneset-based methods for whole genome sequencing studies of rare diseases.

Authors who are presenting talks have a * after their name.

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