The difficulties associated with the clinical application of next generation sequencing (NGS) approaches can be substantial. However, the technology holds great potential to improve outcomes and risk management for inherited heart disease patients and their families. This PhD thesis focuses on three critical challenges associated with the clinical application of NGS technologies; (i) Understanding correlations between genetics and the clinical phenotype; (ii) the impact of uncertainty created by NGS-based genetic testing on the patient; and (iii) developing evidence-based approaches for improving current and future methods for returning complex genetic results. Two studies focused on understanding correlations between genetics and the clinical phenotype. Firstly, the study reported in Chapter two, which aimed to analyse genetic and phenotypic findings from a consecutive cohort of hypertrophic cardiomyopathy (HCM) families who had undergone comprehensive cardiac panel testing. We showed that increasing the number of genes included on HCM panels beyond the eight established sarcomere genes does not increase the diagnostic yield. However, identification of variants of uncertain significance increased dramatically from 13% to 36%. This result has important clinical implications. Increasing the number of genes screened does not necessarily improve the chance of identifying a family’s cause of disease but is likely to increase identification of uncertain results that can increase the complexity of discussions around inheritance and risk. We also showed that identification of multiple rare variants was associated with earlier disease onset, greater likelihood of family history of sudden cardiac death (SCD) and overall worse event-free survival (5/18 events versus 29/170 events, log-rank test p=0.008). Clinical heterogeneity is a hallmark feature of HCM and here we show one factor that can contribute to worse outcomes. The study reported in Chapter three aimed to describe the diverse genetic and phenotypic features of an international cohort of patients with a truncating variant in the desmoplakin (DSP) gene traditionally considered to cause arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first complete report of the diverse phenotype spectrum of DSP cardiomyopathy, suggesting that truncating variants in DSPshould be considered its own entity. We show that the phenotype associated with truncations in DSP is severe, with a high rate of SCD and characterised by left ventricular dysfunction and structural left ventricular involvement when compared with ‘classic’ ARVC. In addition, we show the functional domain in which DSP truncating variants reside has clinical significance. Key results from Chapter two and three emphasise the importance of correlating genetic variants with phenotype information. Data from this work is a step towards precision medicine whereby patients’ risk will be assessed and managed based on their genotype. In Chapter four we designed a qualitative study to explore attitudes, preferences, recall and psychosocial consequences of uncertain genetic results returned to HCM probands. The major themes we identified were knowledge and recall of complex genetic information, individual experiences with HCM genetic testing and communication and the value of information. In addition, those with uninformative results had a unique set of issues. We found that HCM probands undergoing genetic testing require additional support and information beyond the current practice model employed in the multidisciplinary specialist clinic setting. Importantly, many of the probands interviewed who received an uninformative or uncertain genetic result showed poor recall and understanding of genetic information. The final aim was to determine if a genetic counsellor led intervention using a communication aid for the delivery of HCM genetic test results improves the ability and confidence of the proband to communicate genetic results to at-risk relatives. This work is presented in Chapter five. We developed a study protocol for a randomised controlled trial with the primary outcome being the ability and confidence of the proband to communicate genetic results to at-risk relatives. We focused on transforming findings from the previous chapters into improved clinical practice. The a priori primary outcome did not show statistically significant differences between the control and intervention group, though the majority of probands in the intervention group achieved fair communication scores and had higher genetic knowledge scores than those in the control group. Importantly, we found that 29% of at-risk relatives were not informed of a genetic result in their family. We highlight the significant gap in our current approach to supporting family communication about genetics. The studies presented highlight that whilst genetic testing has significant potential for benefit in inherited heart disease families in terms of diagnosis, management and family screening there are issues to address in order to improve the clinical utility and application of a comprehensive approach to testing. Overall, the work contributes to understanding the genetic architecture of inherited heart diseases, the clinical impact of NGS results for patients, as well as highlighting that more work is needed to improve the clinical utility from an NGS approach to genetic testing
