34 November 2019 Getting Personal: Omics of the Heart

Jane Ferguson:                  Hi there. Welcome to the November 2019 issue of Getting Personal: Omics of the Heart. I'm Jane Ferguson. This is your podcast from Circulation: Genomic and Precision Medicine. Let's get started.
                                                First up from Eric Curruth, Christopher Haggerty and colleagues from Geisinger, we have a paper entitled, “Prevalence and Electronic Health Record-based Phenotype of Loss-of-function Genetic Variance in Arrhythmogenic Right Ventricular Cardiomyopathy-associated Genes”. In this study, the team set out to understand the phenotypic consequences of variants and desmosome genes which has been associated with a arrhythmogenic right ventricular cardiomyopathy or ARVC. In clinical genetic testing, secondary findings of pathogenic or likely pathogenic variants in desmosome genes are recommended for clinical reporting. However, relatively little is known about the phenotypic consequences of these variants in a general clinical population.
                                                The team obtained whole exome sequencing data for over 61,000 individuals from the DiscovEHR cohort, part of the Geisinger MyCode Community Health Initiative. They then screened individuals for a putative loss of function variants in PKP2, DSC2, DSG2, and DSP. They evaluated ARVC diagnostic criteria using previously conducted ECG and echocardiograms and performed a phenom-wide association study or PHeWAS using EHR derived phenotypes. They found 140 people with an ARVC variant in one of the four genes, none of whom had an existing diagnosis of ARVC in the EHR.
                                                Further, there were no measurable differences in their ECG or echocardiogram findings compared with matched controls. There were also no associations with any heart disease phenotypes as assessed by PHeWAS. Overall, they report a prevalence of ARVC loss of function variants of around one in 435 in a general clinical population of predominantly European descent, but they did not find evidence that these variants associated with specific phenotypes. Thus, the clinical relevance of putative loss of function variants in desmosome genes still remains to be determined.
                                                The next paper is titled, “MRAS Variants Cause Cardiomyocyte Hypertrophy in Patients-specific iPSC-derived Cardiomyocytes”. Additional evidence for MRS as a definitive Noonan syndrome susceptibility gene. This comes from Erin Higgins, Michael Ackerman, and colleagues from the Mayo Clinic. They were interested in understanding whether a recently identified Noonan syndrome variant in the MRS gene was necessary and sufficient to cause Noonan syndrome with cardiac hypertrophy. They generated induced pluripotent STEM cell or IPS C lines from patient derived cells carrying the glycine 23 veiling variant and MRS. In addition to isogenic control cells where the pathogenic variant was corrected back to wild-type using CRISPR CAS nine gene editing, they also created a disease model cell line by introducing the MRS variant into unrelated control cells.
                                                They then comprehensively characterized the phenotypes of the three cell lines using a variety of approaches including microscopy, immunofluorescence, single cell RNA seek, Western blot, qPCR, and live cell calcium imaging. Both the patient derived and the disease model IPS cardiomyocytes were larger than control cells and demonstrated changes in gene expression and intracellular pathway signaling characteristic of cardiac hypertrophy. The patient and disease model cells also displayed impaired calcium handling. Through in-vi