Genetic variation, pathogenicity, and pathophysiology of human channelopathies

Abstract

The application of genome science to inherited heart disease requires accurate genetic evaluation and understanding of physiologic resulting from genetic variation. Using a Long QT syndrome phenotype that is very suggestive of an underlying genetic cause of compound heterozygous KCNQ1 variants, we identified a class of genetic lesions not identified by next-generation sequencing techniques. In order to implement the results of genetic testing into health care practice, variant causality must be evaluated by statistical or functional approaches. Two approaches to functionally establish causation and define the molecular and transcriptional mechanisms of novel variants identified in human channelopathies are heterologous expression and stem cell-derived cardiomyocyte models. Heterologous expression of de novo KCNB1 missense variants identified in epileptic encephalopathy severely altered KV2.1 function. Mutant KV2.1 channels result in lost ion selectivity and gained depolarizing inward cation conductance. We identified a rare variant in the cardiac transcription factor TBX5 in an SCN5A-negative Brugada Sydrome (BrS) family. Functional and transcriptional evaluation after genome editing in patient-derived cardiomyocytes demonstrated that the rare TBX5 missense causes reduced cardiac sodium expression and current, the hallmark of BrS. In summary, the collective work participates in the advancement of scientific knowledge for translation into clinical practice.