The role of genetics in inherited cardiomyopathies

Abstract

While the role of genetics in inherited cardiomyopathies has been recognised as a diagnostic tool for decades, utility of genetics as a prognostic and/or therapeutic tool is relatively new. This thesis takes a gene-specific approach to demonstrate the role genetics can play beyond diagnosis and family screening, and demonstrates gaps and limitations of our knowledge at present in this highly dynamic field.

A review of the utility of genetics in diagnosis, prognosis, and clinical management in inherited cardiomyopathies was conducted. This identified genotype-specific disease sub-groups with strong evidence supporting the use of genetics in clinical management and highlighting that at present the spectrum of clinical utility is not reflected in current guidelines.

A case series of FLNC truncating variants is presented and confirms a distinct left-sided arrhythmogenic cardiomyopathy phenotype with high risk of severe cardiac outcomes including end-stage heart failure and sudden cardiac death. This presents an exciting example of insights that can be gleaned from better understanding genotype-specific disease sub-groups, with benefit for patient management and outcomes.

A cohort of patients with heterozygous ALPK3 loss-of-function variants is described and highlights potential issues that should be considered before this mechanism is definitively associated as a monogenic cause of hypertrophic cardiomyopathy. This includes variable expression with potential for considerable incomplete penetrance, as well as challenges identified due to transcript evolution and correction.

Classification of inherited cardiomyopathies to specific gene and variant type is increasing the value of genetic testing beyond family screening and quickly becoming an important tool in improving diagnosis and management of patients. Although, there are significant gaps in current knowledge which need to be addressed, and limitations due to the rapidly evolving nature of the field.