MAP3K7 Loss of Function Causes Dilated Cardiomyopathy
- 1Garvan Institute of Medical Research and University of New South Wales, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, Uni
Abstract
Background and AimsDilated 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.
MethodsWe integrated four lines of genetic evidence: de novo variation, common variant association, familial segregation, and rare variant enrichment, alongside functional characterisation.
ResultsIn 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 (p.(Tyr125Cys), estimated LOD = 2.7). Rare damaging non-truncating variants were enriched in DCM versus INTERVAL (OR 22, P=0.007) and gnomAD controls (OR 14, P=6.2x10-), while truncating variants were associated with DCM in Genomics England 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.
ConclusionMultiple 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 ABSTRACTO_ST_ABSKey Question: Do MAP3K7 variants cause isolated dilated cardiomyopathy?C_ST_ABSMAP3K7 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 FindingWe 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 nine clinically affected genotype-positive individuals in one pedigree (estimated LOD score 2.7). Further, p.(Cys266del) was observed in three affected individuals in one family and a de novo paediatric case.
Take-Home MessageLoss-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.
O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/26361780v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): [email protected]@7f9d0eorg.highwire.dtl.DTLVardef@200470org.highwire.dtl.DTLVardef@3813c_HPS_FORMAT_FIGEXP M_FIG C_FIG
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BibTeX
@misc{josephs2026map3k7,
title = {{MAP3K7 Loss of Function Causes Dilated Cardiomyopathy}},
author = {K. S. Josephs and C. C. Smith-Diaz and A. Woods and C. Prince and S. L. Zheng and R. Buchan and E. Cavanagh and S. Elahi and E. Jennings and H. Procter and J. S. McTaggart and R. Janan and P. Theotokis and A. Baker and N. Henden and K. A. McGurk and K. Prescott and Newcastle Clinical Genetics Team and V. Jobanputra and P. James and T. Thompson and D. Zentner and U. Tayal and B. P. Halliday and S. K. Prasad and D. P. O'Regan and R. T. Lumbers and P. J. R. Barton and K. Richardson and S. Klaassen and A. Rico-Armada and P. E. F. Daubeney and V. L. Hartill and S. P. Page and A. M. Roberts and D. Carling and J. Ingles and J. S. Ware and GoDCM Consortium},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.02.26361780},
url = {https://www.medrxiv.org/content/10.64898/2026.09.02.26361780v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - MAP3K7 Loss of Function Causes Dilated Cardiomyopathy
AU - K. S. Josephs
AU - C. C. Smith-Diaz
AU - A. Woods
AU - C. Prince
AU - S. L. Zheng
AU - R. Buchan
AU - E. Cavanagh
AU - S. Elahi
AU - E. Jennings
AU - H. Procter
AU - J. S. McTaggart
AU - R. Janan
AU - P. Theotokis
AU - A. Baker
AU - N. Henden
AU - K. A. McGurk
AU - K. Prescott
AU - Newcastle Clinical Genetics Team
AU - V. Jobanputra
AU - P. James
AU - T. Thompson
AU - D. Zentner
AU - U. Tayal
AU - B. P. Halliday
AU - S. K. Prasad
AU - D. P. O'Regan
AU - R. T. Lumbers
AU - P. J. R. Barton
AU - K. Richardson
AU - S. Klaassen
AU - A. Rico-Armada
AU - P. E. F. Daubeney
AU - V. L. Hartill
AU - S. P. Page
AU - A. M. Roberts
AU - D. Carling
AU - J. Ingles
AU - J. S. Ware
AU - GoDCM Consortium
PY - 2026
DA - 2026/09/02
PB - medRxiv
DO - 10.64898/2026.09.02.26361780
UR - https://www.medrxiv.org/content/10.64898/2026.09.02.26361780v1
AB - Background and AimsDilated 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. MethodsWe integrated four lines of genetic evidence: de novo variation, common variant association, familial segregation, and rare variant enrichment, alongside functional characterisation. ResultsIn 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 (p.(Tyr125Cys), estimated LOD = 2.7). Rare damaging non-truncating variants were enriched in DCM versus INTERVAL (OR 22, P=0.007) and gnomAD controls (OR 14, P=6.2x10-), while truncating variants were associated with DCM in Genomics England 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. ConclusionMultiple 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 ABSTRACTO_ST_ABSKey Question: Do MAP3K7 variants cause isolated dilated cardiomyopathy?C_ST_ABSMAP3K7 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 FindingWe 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 nine clinically affected genotype-positive individuals in one pedigree (estimated LOD score 2.7). Further, p.(Cys266del) was observed in three affected individuals in one family and a de novo paediatric case. Take-Home MessageLoss-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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/26361780v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): [email protected]@7f9d0eorg.highwire.dtl.DTLVardef@200470org.highwire.dtl.DTLVardef@3813c_HPS_FORMAT_FIGEXP M_FIG C_FIG
ER -