De novo and inherited variants in coding and regulatory regions in genetic cardiomyopathies

Nirmal Vadgama, Mohamed Ameen, Lakssham Sundaram, Sadhana Gaddam, Casey A Gifford, Jamal Nasir*, Ioannis Karakikes*

*Corresponding author for this work

Research output: Contribution to JournalArticlepeer-review


BACKGROUND: Cardiomyopathies are a leading cause of progressive heart failure and sudden cardiac death; however, their genetic aetiology remains poorly understood. We hypothesised that variants in noncoding regulatory regions and oligogenic inheritance mechanisms may help close the diagnostic gap.

METHODS: We first analysed whole-genome sequencing data of 143 parent-offspring trios from Genomics England 100,000 Genomes Project. We used gene panel testing and a phenotype-based, variant prioritisation framework called Exomiser to identify candidate genes in trios. To assess the contribution of noncoding DNVs to cardiomyopathies, we intersected DNVs with open chromatin sequences from single-cell ATAC-seq data of cardiomyocytes. We also performed a case-control analysis in an exome-negative cohort, including 843 probands and 19,467 controls, to assess the association between noncoding variants in known cardiomyopathy genes and disease.

RESULTS: In the trio analysis, a definite or probable genetic diagnosis was identified in 21 probands according to the American College of Medical Genetics guidelines. We identified novel DNVs in diagnostic-grade genes (RYR2, TNNT2, PTPN11, MYH7, LZR1, NKX2-5), and five cases harbouring a combination of prioritised variants, suggesting that oligogenic inheritance and genetic modifiers contribute to cardiomyopathies. Phenotype-based ranking of candidate genes identified in noncoding DNV analysis revealed JPH2 as the top candidate. Moreover, a case-control analysis revealed an enrichment of rare noncoding variants in regulatory elements of cardiomyopathy genes (p = .035, OR = 1.43, 95% Cl = 1.095-1.767) versus controls. Of the 25 variants associated with disease (p< 0.5), 23 are novel and nine are predicted to disrupt transcription factor binding motifs.

CONCLUSION: Our results highlight complex genetic mechanisms in cardiomyopathies and reveal novel genes for future investigations.

Original languageEnglish
Article number55
Pages (from-to)55
JournalHuman Genomics
Early online date10 Nov 2022
Publication statusPublished - 10 Nov 2022

Bibliographical note

© 2022. The Author(s).


  • Cardiomyopathy
  • De novo
  • Noncoding
  • Oligogenic
  • Regulome
  • Research
  • Single-cell
  • Genetic Predisposition to Disease
  • Humans
  • Regulatory Sequences, Nucleic Acid
  • Exome
  • Phenotype
  • Cardiomyopathies/genetics


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