Saturation Mutagenesis of MYH7 to Identify Hypertrophy-causing Variants

Hannah De Jong, Stanford University

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Hypertrophic cardiomyopathy (HCM) is the most common genetic heart defect, and is characterized by a thickening of the left ventricular wall of the heart. In many HCM cases a causal variant can be found in the gene MYH7, which encodes beta cardiac myosin. However, hundreds of different rare variants are observed in MYH7 and not all of them cause HCM. A method to predict pathogenic variants, when integrated with existing patient data, would facilitate better clinical diagnosis and improve our understanding of MYH7 biology. Therefore our aim is to screen all possible single nucleotide variants (SNVs) in MYH7 by performing saturation mutagenesis in a tissue culture model. Cardiomyocytes will be genetically modified in a pooled manner to contain each SNV. They will then be phenotyped for hypertrophy and other markers of HCM, and MYH7 variants associated with a hypertrophy phenotype will become candidates for HCM pathogenicity. Here we present our preliminary phenotyping assay results and discuss our planned methodology.

Abstract Author(s): Hannah De Jong, Alex Dainis, Julian Homburger, Shirley Sutton, Euan Ashley