Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, Missouri, USA.
Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, Missouri, USA.
Am J Med Genet A. 2023 Jan;191(1):259-264. doi: 10.1002/ajmg.a.63006. Epub 2022 Oct 27.
De novo variants in FOXP4 were recently associated with a neurodevelopmental disorder characterized by speech and language delay, growth abnormalities, hypotonia, and variable congenital abnormalities, including congenital diaphragmatic hernia, cervical spine abnormalities, strabismus, cryptorchidism, and ptosis. The variant spectrum in this small cohort was limited to de novo missense except for one frameshift, the inheritance of which was unknown. Variants tested in vitro exhibited reduced repressor transcriptional activity, indicating loss of function is the likely mechanism of disease, but only one frameshift variant was reported. Here, we report four affected individuals from two unrelated families heterozygous for a nonsense variant, c.1893C > G, p.Tyr631*, in FOXP4. The phenotype of the affected children includes developmental delay, feeding difficulties in infancy, and similar facial features. In both cases, the variant was inherited from a parent with mild or even subclinical features. Interestingly, one patient presented with congenital diaphragmatic hernia, as reported in two other FOXP4 patients. This report implicates FOXP4 truncating variants in human disease and highlights the wide phenotypic spectrum and variable expressivity.
最近，FOXP4 中的从头变异与一种神经发育障碍有关，其特征是言语和语言延迟、生长异常、低张力和可变的先天性异常，包括先天性膈疝、颈椎异常、斜视、隐睾和上睑下垂。在这个小队列中，变异谱仅限于从头错义变异，除了一个移码变异，其遗传方式未知。体外测试的变异体显示出降低的阻遏转录活性，表明功能丧失是疾病的可能机制，但仅报告了一个移码变异体。在这里，我们报告了两个无关家庭的四个受影响个体，他们均为 FOXP4 中的无意义变异 c.1893C > G，p.Tyr631* 的杂合子。受影响儿童的表型包括发育迟缓、婴儿期喂养困难和类似的面部特征。在两种情况下，该变异均来自一个具有轻度甚至亚临床特征的父母遗传。有趣的是，一名患者患有先天性膈疝，如另外两名 FOXP4 患者所报告的那样。本报告提示 FOXP4 截断变异与人类疾病有关，并强调了广泛的表型谱和可变的表达性。
