Fig. 5: Spectrum of dominance and recessiveness in genetic CMs.

a, Heatmap of associations between rare variants in recessive CM genes and relevant outcomes in the UK Biobank under a dominant model. Cells are colored according to the effect size of the best (lowest nominal P value) variant class mask for the respective gene–trait association, where red indicates increased disease risk (or higher quantitative value), and blue indicates lower disease risk (or lower quantitative value). Disease outcomes were analyzed using logistic mixed-effects models and Firth’s regression models, while the quantitative MRI traits were analyzed using linear mixed-effects models. Effect sizes for binary traits with P > 0.05 have been made white for clarity. P values represent the overall Cauchy P value of the gene–trait association, while Q values represent the Benjamini–Hochberg FDR adjusted values (see the Methods for the details). IVSmax, maximum interventricular septal mass; LVEDV, left ventricular end diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end systolic volume; LVSV, left ventricular stroke volume; RVEDV, right ventricular end diastolic volume; RVEF, right ventricular ejection fraction; RVESV, right ventricular end systolic volume; RVSV, right ventricular stroke volume. b, Model to summarize putative genotype–phenotype relationships for genes associated with autosomal recessive CM. Monoallelic variants in these genes can yield no detectable phenotype (that is, purely recessive inheritance), cause subclinical related phenotypic effects or act as non-Mendelian disease risk factors, or function as causal variants for adult-onset CM. Genes with more robust monoallelic associations are shown in bold. While identification of embryonic lethal biallelic variant classes is challenging given their absence in clinical records, biallelic truncating variants in genes like BAG3, FLNC and VCL have not been described in patients and lead to severe effects in mouse models. ^aNote that different mechanisms were observed between recessive and dominant inheritance for JPH2 and LDB3: biallelic LOF variants cause DCM, while heterozygous missense variants are associated with HCM (JPH2 (refs. ^4,23)) or LVNC CM (LDB3 (refs. ^108,109)). The monoallelic association for NRAP is based on the study by Koskenvuo et al. ¹⁹.