MAP3K7 Loss of Function Causes Dilated Cardiomyopathy
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
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 d e 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.
GRAPHICAL ABSTRACT
Key Question: Do MAP3K7 variants cause isolated dilated cardiomyopathy?
MAP3K7 variants are known to cause rare syndromic disease, including cardiospondylocarpofacial syndrome (CSCF). Some patients with CSCF develop dilated cardiomyopathy (DCM), however we do not know whether MAP3K7 variants cause primary or isolated DCM without overt syndromic disease.
Key Finding
We present multiple orthogonal data sources supporting an association between MAP3K7 loss-of-function variants and DCM. The collective evidence for this gene-disease association encompasses paediatric trio de novo discovery, GWAS, familial segregation, rare variant case-control analysis and variant categorisation in vitro . Strong segregation evidence was obtained for p.(Tyr125Cys), with 9 clinically affected genotype-positive individuals in one pedigree (estimated LOD score 2.7).
Take-Home Message
Loss-of-function variants in MAP3K7 are associated with DCM and several affected individuals lack overt syndromic features. MAP3K7 -related disease may present as apparently isolated DCM across the lifespan. These findings support the incorporation of MAP3K7 testing into DCM diagnostic pipelines.
