Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies

Abstract

Discrete categorization of Mendelian disease genes into dominant and recessive models often oversimplifies their underlying genetic architecture. Cardiomyopathies (CMs) are genetic diseases with complex etiologies for which an increasing number of recessive associations have recently been proposed. Here, we comprehensively analyze all published evidence pertaining to biallelic variation associated with CM phenotypes to identify high-confidence recessive genes and explore the spectrum of monoallelic and biallelic variant effects in established recessive and dominant disease genes. We classify 18 genes with robust recessive association with CMs, largely characterized by dilated phenotypes, early disease onset and severe outcomes. Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively. Our data provide insights into the complex spectrum of dominance and recessiveness in genetic heart disease and demonstrate how such approaches enable the discovery of unexplored genetic associations.

Whole genome sequencing in paediatric channelopathy and cardiomyopathy

“…This also sheds a light on the alternative approach of re-analysis of sequencing data to look for novel discoveries, before fishing the genotype using WGS. The phenotype determination can also help in the sequencing analysis, especially in pediatric cases in which specific metabolic diseases or autosomal recessive conditions may worth a second inspection or further investigations (27).…”

“…For genes with disputed or limited evidence, only genes associated with the phenotypes with sufficient evidence were considered. In paediatrics, genes with recessive inheritance are increasingly recognized and discovered (27). Most of these genes were prioritized already for our analysis, except for those genes established as plausible genes after our study period, like BAG5, CAP2, FLII, KLHL24, LDB3, LEMD2, LMOD2, MYZAP.…”

“…The patient might suffer from burnt-out HCM but it could not be proven. As biallelic variants in MYBPC3 are associated with severe early onset disease (27), a second hit in this gene was reanalyzed again with no additional findings. The variant was classified as VUS based on the ACMG guidelines The flowchart summarizes the result of study recruitment of paediatric cardiac channelopathy and cardiomyopathy patients.…”