Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Abstract

Abstract Background Cardiomyopathies are a set of cardiac diseases which are typically thought to have an autosomal dominant mode of inheritance and usually present in adulthood. However, their genetic architecture is increasingly recognised to be more complex, characterised by incomplete penetrance, variable expressivity and high genetic heterogeneity. In addition, there has been a recent rapid rise in genes associated with cardiomyopathy via a recessive, rather than dominant, mode of inheritance. However, there is increasing evidence that the classical recessive/dominant dichotomy in many Mendelian-like diseases is an oversimplification, with reports of clinically relevant phenotypes, albeit milder, in heterozygous carriers of known recessive variants. Purpose Investigate the genetic landscape of recessive cardiomyopathy and explore the putative spectrum of dominance and recessiveness in cardiomyopathies. Methods Published genetic studies of cardiomyopathies caused by biallelic genotypes were systematically analysed. For established recessive cardiomyopathy genes, monoallelic associations with relevant cardiac phenotypes were investigated using the UK Biobank. Results After appraisal, we characterised 17 genes that are robustly associated with recessive cardiomyopathy based on exome or genome sequencing across multiple pedigrees. The recessive cases were characterised by early age of onset (mean (SD) 12.5±15.1 years), poor outcomes (42.8% reported deceased) and predominance of dilated cardiomyopathy (11/17 genes). Studies in understudied groups, particularly bottleneck populations and regions of high consanguinity, were particularly informative for novel gene discovery. For several of the recessive genes, monoallelic variants were associated with cardiac phenotypes in the UK BioBank, for example, ALPK3 and SLC30A5 with hypertrophic cardiomyopathy and LMOD2 with dilated cardiomyopathy, the latter two are novel monoallelic associations. Analysing individuals with biallelic variants in established dominant sarcomeric cardiomyopathy genes revealed an earlier age of onset compared to monoallelic carriers (median (IQR) 13.5 (1.0-30.0) vs 37.5 (23.6-49.8) years), although with variability between genes and variant classes. Conclusions Disease genes associated with recessive inheritance are becoming an increasingly important aspect of the genetic architecture of cardiomyopathies, but there is also evidence of the presence, and spectrum, of phenotypes in monoallelic carriers of variants for several of these same genes. These findings illustrate the complexities of genotype-phenotype associations in cardiomyopathy and the need for more comprehensive and informed clinical genetic testing, particularly for patients from diverse and understudied ancestries.Recessive cardiomyopathy cases