Genetic architecture of heritable cardiac diseases

A key focus of our research is exploring the genetic architecture of cardiac diseases - we aim to discover, validate and characterise disease-associated genes and explore the complexity of these genetic across phenotype, inheritance/zygosity and disease mechanisms. This includes defining gene-disease associations for cardiomyopathies through rare variant association studies and evidence curation - DCM/HCM (Circulation 2020, EHJ 2017, Genet. Med. 2016), LVNC (Genet. Med. 2021, Review), contribution to ClinGen curation activities for cardiomyopathies and arrhythmias, and expanding research in diverse populations (EHJ 2023).

Featured study: Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies - Lipov et al, Nature Cardiovascular Research 2023

Beyond Mendelian Genetics

Rare Mendelian-like coding variants explain only a fraction of the cases and overall genetic risk in heritable cardiac diseases. In most individuals, we believe disease risk is determined by a threshold model (below), i.e. varying combinations of genetic risk factors of different effect size and population frequency together with non-genetic risk factors. To enable comprehensive genetic risk profiling in patients, families and the population at large, we need large-scale discovery, characterisation and implementation efforts for these non-Mendelian factors. Current areas of focus include common variation through GWAS, variants and genes of intermediate effect size, and rare variation in the non-coding genome.

Featured study: Redefining the Genetic Architecture of Hypertrophic Cardiomyopathy: Role of Intermediate-Effect Variants - Garcia-Hernandez et al, Circulation 2025, (plus recommendations for clinical implementation: Circulation 2026)

Variant Interpretation

The interpretation of rare coding variants remains a critical task in cardiac genomics - for clinical genetic testing of cardiomyopathy and arrhythmia patients/families, in the context of molecular autopsy (genetic testing after sudden cardiac death) and increasingly for incidental findings as genomic screening becomes mainstream. We seek to develop new methodologies to enhance variant classification and develop gene/disease-specific pipelines that integrate orthogonal lines of evidence, including emerging high-throughput functional assays, large-scale genomics datasets and cutting-edge bioinformatics algorithms.

Featured study: Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls - Walsh et al, Genet. Med 2021

Genetics of Brugada syndrome

Brugada syndrome has been the most challenging of the heritable cardiac diseases with regards to uncovering its genetic aetiology and exemplifies the approaches needed to explore the non-Mendelian genetics of these conditions. Our research in this domain focuses on identifying novel disease genes (only one validated gene, SCN5A, has been established in three decades of research) and in exploring intermediate effect and non-coding genetic risk factors at the SCN5A-SCN10A locus (medRxiv 2026), as part of multi-centre collaborations with colleagues in London, Amsterdam, Thailand, and France.