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Heterozygous MAP3K20 variants cause ectodermal dysplasia, craniosynostosis, sensorineural hearing loss, and limb anomalies.

Daniel BrooksElizabeth BurkeSukyeong LeeTanya N EbleMelanie O'LearyIkeoluwa A Osei-OwusuMichael J BamshadShweta U DharLisa EmrickDavid BickMichelle NehrebeckyEllen MacnamaraDídac Casas-AlbaJudith ArmstrongCarolina PratAntonio Federico Martínez-MonsenyFrancesc PalauPengfei LiuDavid Adamsnull nullSeema LalaniJill Anne RosenfeldLindsay C Burrage
Published in: Human genetics (2024)
Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development.
Keyphrases
  • copy number
  • early onset
  • endothelial cells
  • high density
  • genome wide
  • stem cells
  • hearing loss
  • tyrosine kinase
  • intellectual disability
  • transcription factor
  • muscular dystrophy