The molecular genetics of familial cardiomyopathy

Introduction The cardiomyopathies are responsible for approximately 5.9 of 100,000 deaths in the general global population and in sub-Saharan Africa (SSA), these myocardial diseases are observed in 21.4% of patients with heart failure. The precise etiology of the cardiomyopathies is currently not well known and through our research we aim to contribute to the genetic landscape and bridge the gaps in knowledge for the different cardiomyopathies as SSA could provide some very important insights into the cardiomyopathies and identify other possible disease mechanisms. Methods Through next generation sequencing techniques such as whole exome sequencing and targeted resequencing we studied three South African families with severe cardiomyopathy. Clinical diagnosis and recruitment of cardiomyopathy patients into the study was done at Groote Schuur Hospital, Cape Town by a panel of experts. Next generation sequencing data was analysed and filtered through various stringent criteria and the final list of variants were validated through Sanger sequencing. Results In the first multi-generational family with severe dilated cardiomyopathy (DCM) (DCM 334), we identified a pathogenic DMPK c.1067C>T(p.P356L) variant in the proband and her affected father. We also screened a cohort of 542 cardiomyopathy probands though Sanger sequencing of the DMPK gene and identified the DMPK c.1477C>T(p.R493C) variant as a variant of unknown significance. We then investigated a three-generation family with four affected family members who were also affected with severe DCM (DCM343). We used whole exome sequencing and identified the pathogenic BAG3 c.925C>T (p.R309Ter) variant as the cause of disease within this family. Viral infection, anti-hypertensive medication and genetic modifiers in RYR1 and NEB contributed to the variable phenotype among the individuals with the BAG3 variant. Through targeted resequencing we also identified the same pathogenic BAG3 variant in 2 of the 634 cardiomyopathy probands screened. In the third family, we investigated a South African family affected with severe arrhythmogenic cardiomyopathy (ACM). We used whole exome sequencing and targeted resequencing in combination and identified the pathogenic PKP2 c.2197_2202InsGdelCACACC (p.H733Afs*8) as the cause of disease in the proband and his father. We also present evidence of the ALPK3 c.2701C>T(p.Q901Ter) variant modifying the phenotypic manifestation which correlates with the variable penetrance that is seen among ACM families. Conclusion Through this project, we have identified many firsts. To the best of our knowledge, we are the first to show that DMPK is associated with primary DCM in severely affected young patients. As a first for South Africa, we not only identified the pathogenic BAG3 variant in a family with severe DCM, but we also identified the same variant in two additional probands, raising the possibility of a founder effect. In the third and final family with ACM, we identified the pathogenic PKP2 variant as the cause of disease within this family with the novel ALPK3 variant acting as a possible modifier. Our research has added to what is currently known about the cardiomyopathies in Africa but there is still much work to be done as we believe we have just scratched the tip of the iceberg