Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD, USA.
Hum Genet. 2024 Mar;143(3):279-291. doi: 10.1007/s00439-024-02657-2. Epub 2024 Mar 7.
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 中的双等位致病性变异，该基因编码丝裂原活化蛋白激酶，是导致分裂手-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明确与表型相关联。在这里，我们描述了 MAP3K20 的激酶结构域和亮氨酸拉链结构域之间的连接区的杂合新生变异相关的表型谱。我们报告了五个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，他们在该基因的这一特定区域有杂合新生变异。这些个体表现出既有共同点又有独特表现的临床表现，突出了该疾病的复杂性和变异性。我们提出 MAP3K20 参与内皮-间充质转化提供了这些特征的合理病因。这些发现共同描绘了一种疾病，它既扩大了与 MAP3K20 相关的表型谱，又强调了进一步研究其在人类早期发育中作用的必要性。
