Background: MAP3K7, a member of kinase family gene, is a well-known causative gene for Cardiospondylocarpofacial (CSCF) and Frontometaphyseal dysplasia 2 (FMD2), mainly characterized by multimalformations on skeletal development, facial dysmorphism, cardiac abnormalities, hearing loss, intellectual disability. However, its involvement in Disorders/ Differences of Sex Development (DSD) has been underscored.
Aim: To report three new cases carrying MAP3K7 novel variants resulting to syndromic DSD.
Methods: Clinical information was obtanied. DNA was extracted from blood for whole exome sequencing. Luciferase assay using TOPFLASH/FOPFLASH reporter was performed to investigate the Wnt signalling pathway.
Results: The three male patients included one Mexican, one American (found via GeneMatcher), and one Vietnamese. All presented with either CSCF or FMD2 with DSD phenotype. One or more DSD symptoms were observed including cryptorchidism, micropenis, hypospadias, and small testis. Three novel heterozygous variants were identified: NM_145331.3:c.195A>G, c.250G>A, c.574A>G. We found several CSCF/ FMD2 cases reported previously also had DSD symptoms such as cryptorchidism (Y113D), small testis (V50del). Interestingly, DSD were observed in male only, and all the affected ones with DSD have the variant located on kinases domain. TOPFLASH/ FOPFLASH assay showed the activation of beta catenin/ Wnt signalling, the main mechanism driving the female sex development, in the mutants compared to the wildtype.
Conclusion: We report three new cases with novel MAP3K7 variants presenting with syndromic DSD. The activation of beta catenin/ Wnt signalling might explain the undervirilized phenotype in the patients, suggesting MAP3K7 might involve in male sex development. However, further investigation is needed to make a solid conclusion.