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While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7–IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects. [ABSTRACT FROM AUTHOR]

This document is a reply to a letter regarding the pathogenicity of inherited TRAF7 mutations in congenital heart disease. The authors of the reply defend their previous manuscript, which reported the association of TRAF7 variants with congenital heart disease based on experimental data and in silico tools. They argue that their findings are supported by previous research on TRAF7 mutations in syndromic cases and cancer. They also address specific criticisms and limitations of their study, emphasizing the need for further experimental research to understand the mechanisms and phenotypic spectrum of TRAF7 mutations. [Extracted from the article]