Research into the genetic aetiology of cardiomyopathies, and the clinical applications that derive from this, has entered an exciting but highly challenging new phase in recent years. The emergence of large-scale datasets—population genetic databases like gnomAD, deeply phenotyped registries like the UK Biobank as well as genetic data from increasingly large and diverse patient cohorts—has transformed research studies and enabled robustly designed analyses to define gene and variant disease associations. However, these resources have also highlighted that cardiomyopathy-associated genetic variants are far more common in the population than previously anticipated, suggesting more complex models of disease aetiology are required to explain the large variability in penetrance and phenotype expressivity observed in variant carriers.

To tackle these issues, research in diverse patient and population groups is needed to explore the complex associations between genotype and phenotype and evaluate how common and rare genetic variation and non-genetic risk factors combine to define disease risk. This special issue entitled New Insights into the Genetics of Cardiomyopathies contains seven selected papers that explore these issues for the major sub-types of cardiomyopathies—hypertrophic (HCM), dilated (DCM), arrhythmogenic (ACM) and left ventricular non-compaction (LVNC) cardiomyopathy.

Population founder variants provide valuable research settings for exploring the factors involved in incomplete penetrance and variable expressivity. Lopera-Maya and colleagues [1] analysed carriers of the PLN:p.Arg14del variant (a prominent cause of DCM/ACM in the Netherlands) using data from the Lifelines cohort and the PLN patient registry. They found that asymptomatic carriers of the p.Arg14del variant had a significantly shorter electrocardiogram QRS duration (− 5.7 ms) compared to asymptomatic non-carriers as well as symptomatic carriers, suggesting a shorter QRS can prevent the onset of disease, although this could not be explained by differences in QRS polygenic scores.

Jansen and colleagues [2] also made use of Dutch founder variants in an exploratory study to identify peripheral biomarkers of disease severity in HCM. Utilising the BIO FOr CARe resource (a registry of HCM MYBPC3 founder variant carriers established to identify biomarkers of disease development and progression), the study assessed circulating acylcarnitine levels in 124 individuals with varying phenotypes. Eight such acylcarnitines were found to be associated with disease severity, with increased plasma levels detected in patients with either severe or mild disease compared to phenotype-negative carriers. These markers of dysregulated fatty acid metabolism in the heart could have utility in the clinical monitoring of variant carriers in HCM families.

Akinrinade and colleagues [3] explored the differences in cardiomyopathy genetics by sex and age at diagnosis, utilising data from the Ontario Heart Centre Biobank and the UK 100,000 Genomes Project. Among the key findings was a higher yield of deleterious variants in core disease genes in paediatric HCM (but not DCM) cases compared to adults, driven by an increased burden of variants in MYH7 and MYL3. The study also detected no overall difference in genetic yield by sex, although Z-disc gene variants were found to be enriched in females.

Accurate variant classification remains a pressing issue in cardiomyopathy clinical genetics and interpreting the clinical relevance of detecting multiple rare variants in patients is challenging for clinicians and clinical geneticists. Nagoya, Hoorntje and colleagues [4] assessed a large cohort of arrhythmogenic right ventricular cardiomyopathy (ARVC) cases (n = 331) derived from published studies and the Dutch ARVC Registry that carried multiple apparently pathogenic variants. Upon reclassification with contemporary guidelines, only 29% of cases retained multiple pathogenic variants, but these were associated with more severe clinical outcomes, highlighting the clinical relevance of accurate variant interpretation.

Novel and recently implicated cardiomyopathy genes tend to have very low prevalence in patient cohorts, and therefore case studies/series are essential for understanding their unique clinical characteristics. Zahavich and colleagues [5] described a case series of one of the more intriguing cardiomyopathy genes—loss-of-function variants in VCL which cause paediatric DCM but usually lead to the rapid recovery of cardiac function with heart failure medication. Further research will be needed to understand the factors underlying this age-dependent phenotype presentation and the highly variable expressivity in pedigrees where variants are inherited.

ALPK3 was one of the first cardiomyopathy genes robustly associated with recessive inheritance and was later shown to demonstrate a spectrum of effects with heterozygous loss-of-function variants causing late-onset HCM. Poleg, Eskin-Schwartz and colleagues described an intriguing family pedigree with infantile-onset HCM in twin sisters caused by compound heterozygous variants in ALPK3—a nonsense coding variant and an intronic variant shown by in vitro assay to affect splicing and lead to a truncated protein [6]. The probands’ uncle was a heterozygous carrier of the nonsense variant and diagnosed with HCM at 61 years (their father and grandfather also died suddenly).

This special collection concludes with a review article on the genetics of LVNC cardiomyopathy (in press—CATR-D-23–00320), describing recent meta-analyses that have illuminated the genetic aetiology of this complex and controversial phenotype and demonstrated the potential of genetic testing to support diagnosis of a wide array of conditions that can present with left ventricular hypertrabeculation.