MAP3K7 – Cardiospondylocarpofacial Syndrome

Cardiospondylocarpofacial syndrome (CSCFS) is an ultrarare autosomal dominant disorder characterized by growth retardation, dysmorphic facial features, valve dysplasia, carpal and tarsal fusions, vertebral synostosis, joint hypermobility, and connective tissue manifestations. Heterozygous variants in MAP3K7, encoding TGF-β-activated kinase 1 (TAK1), underlie CSCFS and define its molecular basis (Cardiospondylocarpofacial Syndrome).

A multi-patient exome sequencing study identified heterozygous MAP3K7 variants in six unrelated individuals from four families (6 probands PMID:27426734), establishing locus homogeneity. Subsequent case reports described six additional de novo or likely de novo variants in independent probands (6 probands PMID:29467388, PMID:32299812, PMID:34558790, PMID:36320120, PMID:37160697, PMID:38383446), totaling 12 unrelated probands.

Inheritance of CSCFS is autosomal dominant with predominantly de novo occurrence; no extensive familial segregation beyond single cases has been reported. Variant classes include missense substitutions, small in-frame deletions, splice-site alterations, and the first reported frameshift mutation. Representative pathogenic change: c.125_127del (p.Val42del) (PMID:32299812).

Functional studies of the recurrent c.737-7A>G splice variant demonstrate generation of a novel splice acceptor, insertion of two residues in the kinase domain, impaired TAK1 autophosphorylation, loss of TAB1 binding, and downstream dysregulation of TGFβ-mediated α-SMA cytoskeleton assembly and autophagy in patient fibroblasts (PMID:32105826). Missense variants similarly disrupt kinase activity and p38 MAPK signaling, supporting haploinsufficiency as the pathogenic mechanism.

No conflicting or alternative associations have been reported for MAP3K7 in CSCFS. The concordant genetic and experimental data fulfill ClinGen criteria for a Strong gene–disease association.

Key take-home: De novo heterozygous MAP3K7 variants cause autosomal dominant CSCFS, and MAP3K7 genetic testing is essential for diagnosis and may guide future TAK1-targeted therapies.

References

• American journal of human genetics • 2016 • Heterozygous Mutations in MAP3K7, Encoding TGF-β-Activated Kinase 1, Cause Cardiospondylocarpofacial Syndrome PMID:27426734
• European journal of human genetics • 2018 • A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder. PMID:29467388
• Cold Spring Harbor molecular case studies • 2020 • A novel variant in MAP3K7 associated with an expanded cardiospondylocarpofacial syndrome phenotype. PMID:32299812
• Biochimica et biophysica acta. Molecular basis of disease • 2020 • Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: MAP3K7 c.737-7A>G variant alters the TGFβ-mediated α-SMA cytoskeleton assembly and autophagy PMID:32105826
• American journal of medical genetics. Part A • 2022 • Expanding the phenotypic spectrum of cardiospondylocarpofacial syndrome: From a detailed clinical and radiological observation of a boy with a novel missense variant in MAP3K7. PMID:34558790
• Clinical genetics • 2023 • A novel MAP3K7 mutation in a child with cardiospondylocarpofacial syndrome and orofacial clefting. PMID:36320120
• Prenatal diagnosis • 2023 • Early and severe tricuspid valve dysplasia in a fetus with cardiospondylocarpofacial syndrome due to a variant c.616T>G p.(Tyr206Asp) in MAP3K7. PMID:37160697
• Human genome variation • 2024 • A severe case of cardiospondylocarpofacial syndrome with a novel MAP3K7 variant. PMID:38383446

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