Department of Microbiology and Molecular Biology, College of Life Sciences, Brigham Young University, Provo, Utah, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Am J Med Genet A. 2022 Oct;188(10):2958-2968. doi: 10.1002/ajmg.a.62919. Epub 2022 Jul 29.
Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.
先天性膈疝 (CDH) 可单独发生，也可与其他出生缺陷同时发生 (CDH+)。只有一部分 CDH 病例可以确定分子病因。这部分归因于对参与膈肌发育的基因的不完全了解。在这里，我们使用 DECIPHER 数据库中 36 名 CDH+患者的临床和分子数据，以鉴定可能在膈肌发育中发挥作用的基因，并发现新的表型扩展。在这组患者中，我们发现一些患者携带可能有害的序列或拷贝数变异，这些变异影响 CREBBP、SMARCA4、UBA2 和 USP9X。这些基因在膈肌发育中的作用得到了以下证据的支持：它们在发育中的小鼠膈肌中有表达，它们与先前发表的和经过验证的机器学习算法的数据中已知的 CDH 基因相似，或者在其他患有相关遗传疾病的个体中存在 CDH。我们的结果表明，如何使用 DECIPHER 和其他公共数据库来识别新的表型扩展，并提示 CREBBP、SMARCA4、UBA2 和 USP9X 在膈肌发育中发挥作用。
