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.

MAP3K20编码丝裂原激活蛋白激酶，其双等位基因致病性变异是导致裂手足畸形 (SHFM)、听力损失、指甲异常或先天性肌病的罕见原因。然而，该基因的杂合变异尚未与表型明确相关。在这里，我们描述了与 MAP3K20 激酶结构域和亮氨酸拉链结构域之间的连接区杂合从头变体相关的表型谱。我们报告了五名具有不同临床特征的个体，包括颅缝早闭、肢体异常、感音神经性听力损失和外胚层发育不良样表型，他们在该基因的特定区域具有杂合的从头变异。这些个体表现出共同和独特的临床表现，突出了疾病的复杂性和变异性。我们认为 MAP3K20 参与内皮-间质转化为这些特征提供了合理的病因。总之，这些发现表征了一种疾病，它既扩大了与MAP3K20相关的表型谱，又强调需要进一步研究其在人类早期发育中的作用。