When genetic burden reaches threshold

Abstract

Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

Keywords: Genetic modifiers; Genetics; Genome-wide association studies; Inherited cardiomyopathies; Rare cardiac disease; Ventricular arrhythmias.

Figure 1

The increasingly complex aetiology of rare cardiac genetic diseases. Mendelian variants (blue) are ultra-rare in the population and have large effect sizes, though often not sufficient in isolation to yield a disease phenotype. Mendelian genes and variants can be identified through analysis of family pedigrees or burden analysis in case–control studies and further validated with functional assays. Common variants (red) with individually small effect sizes may collectively contribute to disease burden or modulate the effects of Mendelian variants. Intermediate effect variants (green) are emerging variant classes that usually have population frequencies and effect sizes between rare Mendelian and common variants and may act to increase severity and penetrance. Such variants can be identified by demonstrating enrichment in case cohorts and deleterious effects in established functional assays. These different variant classes can combine to reach the threshold of disease in patients with rare cardiac diseases and contribute to the variable expressivity/severity observed in patients (concept adapted from ref.¹²) Diseases such as HCM and LQTS are often near-Mendelian, where Mendelian variants of large effect sizes can combine with other variant classes to causes disease (1) or act as protective modifiers (e.g. regulatory variants affecting the expression ratio of the mutant vs. non-mutant alleles) (2). In contrast, diseases such as BrS and DCM may exhibit a more complex aetiology where substantial non-Mendelian genetic and non-genetic factors are required to reach disease threshold in the presence of a low penetrance rare variant (3) or in a non-Mendelian disease model.

Figure 2

Increasing genetic complexity of cardiomyopathies. (A) Mendelian variants are identified in less than half of HCM/DCM patients. (B) Additional genetic risk variants may include intermediate effect variants like TNNT2:p.R278C, enriched in European HCM cases  ^,   and often occurring as a secondary sarcomeric variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/12411/). (C) Common susceptibility variants may be identified using direct case–control GWAS. An alternative approach is to identify variants associated with relevant endophenotypes in population cohorts like UK Biobank and then test these for association with disease in patient datasets. The figure shows a Circular Manhattan plot (reproduced with permission from ref.²²) highlighting significant loci associated with six traits of left ventricular function, relevant intermediate phenotypes for cardiomyopathies. Chromosomes are coloured in the outer band, with Manhattan plots for the six phenotypes in concentric circles. Significant loci are highlighted in red, with the closest gene indicated. Loci associated with multiple traits include those harbouring TTN and BAG3. Rare, truncating variants in both TTN and BAG3 are prominent Mendelian causes of DCM, while BAG3 was also significantly associated with DCM in a case-control GWAS.