Heterozygous MAP3K20 Variants Cause Ectodermal Dysplasia, Craniosynostosis, Sensorineural Hearing Loss, and Limb Anomalies

Authors

Daniel Brooks
Elizabeth Burke
Sukyeong Lee
Tanya N Eble
Melanie O'Leary
Ikeoluwa Osei-Owusu
Heidi L Rehm
Shweta U Dhar
Lisa Emrick
David Bick
Michelle Nehrebecky
Ellen Macnamara
Dídac Casas-Alba
Judith Armstrong
Carolina Prat
Antonio F Martínez-Monseny
Francesc Palau
Pengfei Liu
David Adams
Undiagnosed Diseases Network
Seema Lalani
Jill A Rosenfeld
Lindsay C Burrage

Publication Date

3-1-2024

Journal

Human Genetics

DOI

10.1007/s00439-024-02657-2

PMID

38451290

PMCID

PMC11191325

PubMedCentral® Posted Date

3-7-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Ectodermal Dysplasia, Hearing Loss, Sensorineural, Male, Female, Craniosynostoses, Heterozygote, Phenotype, Child, Preschool, Limb Deformities, Congenital, Child, Mutation, Infant, MAP Kinase Kinase Kinases, exome sequencing, ectrodactyly, congenital anomalies, genome sequencing, fibrous dysplasia

Abstract

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.