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

IF 3.8 2区 生物学 Q2 GENETICS & HEREDITY Human Genetics Pub Date : 2024-03-01 Epub Date: 2024-03-07 DOI:10.1007/s00439-024-02657-2
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, Seema Lalani, Jill A Rosenfeld, Lindsay C Burrage
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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.

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杂合子 MAP3K20 变异可导致外胚层发育不良、颅骨发育不良、感音神经性听力损失和肢体异常。
编码有丝分裂原激活蛋白激酶的 MAP3K20 双倍性致病变体是导致手足畸形(SHFM)、听力损失、指甲异常或先天性肌病的罕见原因。然而,该基因的杂合子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(包括颅骨畸形、肢体异常、感音神经性听力损失和外胚层发育不良样表型)的个体,他们在该基因的这一特定区域具有杂合子新生变异。这些患者既有共同的临床表现,也有独特的临床表现,凸显了这种疾病的复杂性和多变性。我们认为,MAP3K20 参与内皮-间充质转化为这些特征提供了合理的病因。这些发现共同描述了一种疾病的特征,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的作用的必要性。
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来源期刊
Human Genetics
Human Genetics 生物-遗传学
CiteScore
10.80
自引率
3.80%
发文量
94
审稿时长
1 months
期刊介绍: Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology. Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted. The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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