FOXP1 Haploinsufficiency Contributes to the Development of Congenital Diaphragmatic Hernia.

IF 0.4 Q4 PEDIATRICS Journal of pediatric genetics Pub Date : 2023-03-28 eCollection Date: 2024-03-01 DOI:10.1055/s-0043-1767731
Katherine E Pendleton, Andres Hernandez-Garcia, Jennifer M Lyu, Ian M Campbell, Chad A Shaw, Julie Vogt, Frances A High, Patricia K Donahoe, Wendy K Chung, Daryl A Scott
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Abstract

FOXP1 encodes a transcription factor involved in tissue regulation and cell-type-specific functions. Haploinsufficiency of FOXP1 is associated with a neurodevelopmental disorder: autosomal dominant mental retardation with language impairment with or without autistic features. More recently, heterozygous FOXP1 variants have also been shown to cause a variety of structural birth defects including central nervous system (CNS) anomalies, congenital heart defects, congenital anomalies of the kidney and urinary tract, cryptorchidism, and hypospadias. In this report, we present a previously unpublished case of an individual with congenital diaphragmatic hernia (CDH) who carries an approximately 3.8 Mb deletion. Based on this deletion, and deletions previously reported in two other individuals with CDH, we define a CDH critical region on chromosome 3p13 that includes FOXP1 and four other protein-coding genes. We also provide detailed clinical descriptions of two previously reported individuals with CDH who carry de novo, pathogenic variants in FOXP1 that are predicted to trigger nonsense-mediated mRNA decay. A subset of individuals with putatively deleterious FOXP4 variants has also been shown to develop CDH. Since FOXP proteins function as homo- or heterodimers and the homologs of FOXP1 and FOXP4 are expressed at the same time points in the embryonic mouse diaphragm, they may function together as a dimer, or in parallel as homodimers, to regulate gene expression during diaphragm development. Not all individuals with heterozygous, loss-of-function changes in FOXP1 develop CDH. Hence, we conclude that FOXP1 acts as a susceptibility factor that contributes to the development of CDH in conjunction with other genetic, epigenetic, environmental, and/or stochastic factors.

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FOXP1单倍体缺陷导致先天性膈疝的形成
FOXP1 是一种参与组织调节和细胞特异功能的转录因子。FOXP1 的单倍体缺陷与一种神经发育障碍有关:常染色体显性智力低下,伴有或不伴有自闭症特征的语言障碍。最近,杂合子 FOXP1 变异也被证明可导致多种结构性先天缺陷,包括中枢神经系统(CNS)异常、先天性心脏缺陷、先天性肾脏和泌尿道异常、隐睾症和尿道下裂。在本报告中,我们发现了一例之前未发表过的先天性膈疝(CDH)患者,该患者携带约 3.8 Mb 的缺失。根据这一缺失以及之前报道的另外两名 CDH 患者的缺失,我们在 3p13 染色体上定义了一个 CDH 关键区域,其中包括 FOXP1 和其他四个蛋白编码基因。我们还对之前报道的两名 CDH 患者进行了详细的临床描述,这两名患者携带 FOXP1 的新致病变异,预计会引发无义介导的 mRNA 衰减。有研究表明,一部分携带可能致癌的 FOXP4 变体的患者也会发展为 CDH。由于 FOXP 蛋白具有同源或异源二聚体的功能,而且 FOXP1 和 FOXP4 的同源物在胚胎小鼠膈肌的同一时间点表达,因此它们可能作为二聚体或作为同源二聚体在膈肌发育过程中共同调节基因表达。并非所有 FOXP1 杂合子功能缺失的个体都会患 CDH。因此,我们得出结论:FOXP1 是一种易感因素,它与其他遗传、表观遗传、环境和/或随机因素共同作用,导致 CDH 的发生。
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期刊介绍: The Journal of Pediatric Genetics is an English multidisciplinary peer-reviewed international journal publishing articles on all aspects of genetics in childhood and of the genetics of experimental models. These topics include clinical genetics, molecular genetics, biochemical genetics, medical genetics, dysmorphology, teratology, genetic counselling, genetic engineering, formal genetics, neuropsychiatric genetics, behavioral genetics, community genetics, cytogenetics, hereditary or syndromic cancer genetics, genetic mapping, reproductive genetics, fetal pathology and prenatal diagnosis, multiple congenital anomaly syndromes, and molecular embryology of birth defects. Journal of Pediatric Genetics provides an in-depth update on new subjects and current comprehensive coverage of the latest techniques used in the diagnosis of childhood genetics. Journal of Pediatric Genetics encourages submissions from all authors throughout the world. The following articles will be considered for publication: editorials, original and review articles, short report, rapid communications, case reports, letters to the editor, and book reviews. The aim of the journal is to share and disseminate knowledge between all disciplines in the field of pediatric genetics. This journal is a publication of the World Pediatric Society: http://www.worldpediatricsociety.org/ The Journal of Pediatric Genetics is available in print and online. Articles published ahead of print are available via the eFirst service on the Thieme E-Journals platform.
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