MAP3K7 Loss of Function Causes Dilated Cardiomyopathy

MAP3K7

Loss of function of MAP3K7 reducing TAK1 kinase activity

Four orthogonal lines of human genetic evidence converge on MAP3K7, which encodes the kinase TAK1, as a cause of apparently isolated dilated cardiomyopathy. Among 117 paediatric cardiomyopathy trios from the 100,000 Genomes Project, two probands carried rare de novo missense variants, a significant excess after Bonferroni correction (p = 0.036). An independent genome-wide association study implicated MAP3K7 as a susceptibility locus for adult dilated cardiomyopathy, and one family showed segregation across nine affected relatives. Truncating variants were associated with disease in the Genomics England cohort and with increased left ventricular volumes in UK Biobank, while disease-associated variants reduced TAK1 kinase activity, supporting a loss-of-function mechanism. Several affected individuals lacked overt syndromic features.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The architecture of the demonstration is exemplary: de novo variants, common variant association, familial segregation, rare variant enrichment and functional evidence, each weak alone but convergent together. The clinical message fits in one sentence: MAP3K7 is no longer only a cardiospondylocarpofacial syndrome gene, and patients without syndromic features carry these variants, so exome and genome interpretation in dilated cardiomyopathy must take it into account. This is a preprint that has not yet been peer reviewed, which argues for waiting for the published version before returning results.

Analysis by Dr Thibaut Benquey