MAP3K7 Loss of Function Causes Dilated Cardiomyopathy

Background and Aims: Dilated cardiomyopathy (DCM) is a genetically heterogeneous cause of heart failure and sudden cardiac death. Many patients remain without a molecular diagnosis. MAP3K7 encodes TAK1, a serine/threonine kinase important for cardiac homeostasis. MAP3K7 variants are an established cause of syndromic disease, including cardiospondylocarpofacial syndrome (CSCF), in which DCM has been occasionally reported. Here, we demonstrate that MAP3K7 variants can cause apparently isolated DCM, expanding the phenotypic spectrum of MAP3K7-related disorders. Methods: We compiled four orthogonal lines of human genetic evidence: de novo variation in paediatric cardiomyopathy; common variant association with adult DCM; familial segregation; and rare variant enrichment in DCM cases, together with functional categorisation of rare variants. Results: In 117 paediatric cardiomyopathy trios from the 100,000 Genomes Project, two probands harboured rare de novo MAP3K7 missense variants, significantly more than expected (Bonferroni-adjusted p=0.036). Independent GWAS implicated MAP3K7 as a susceptibility locus for adult DCM. Across global DCM cohorts, we identified families harbouring rare MAP3K7 variants, including one with segregation in nine affected relatives. Rare damaging non-truncating variants were enriched in DCM cases, while truncating variants were associated with DCM in the Genomics England cohort and increased left ventricular volumes in UK Biobank. DCM-associated variants reduced TAK1 kinase activity, supporting a loss-of-function mechanism consistent with CSCF-associated alleles. Conclusion: Multiple independent lines of evidence establish an association between MAP3K7 loss of function variants and DCM. Several affected individuals lacked overt syndromic features, demonstrating that MAP3K7-related disease may present as apparently isolated DCM across the lifespan and supporting inclusion of MAP3K7 in DCM diagnostic pipelines.