FBN1 contributing to familial congenital diaphragmatic hernia

Abstract

Congenital diaphragmatic hernia (CDH) is a relatively common, life-threatening birth defect. We present a family with recurrent CDH—paraesophageal and central—for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p. Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice—FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.

Exome sequencing identifies de novo pathogenic variants in FBN1 and TRPS1 in a patient with a complex connective tissue phenotype

“…These findings combined with the known pathogenic FBN1 variant allowed the diagnosis of MFS to be established. FBN1 variants and MFS have been reported in association with congenital diaphragmatic hernia (CDH), which was present in our patient (Petersons et al 2003; Faivre et al 2009; Jetley et al 2009; Beck et al 2015). However, this characteristic is not part of the revised Ghent diagnostic criteria or systemic score.…”

Fibrillin-1 Expression Is Decreased in the Diaphragmatic Muscle Connective Tissue of Nitrofen-Induced Congenital Diaphragmatic Hernia

“…14,15 More recently, a frameshift mutation in FBN1 has been reported in familial CDH cases, thus suggesting that alterations in FBN1 gene expression may lead to diaphragmatic defects. 13 In the present study, FBN1 gene expression levels were found to be significantly reduced in PPFs on D13, developing diaphragms on D15, and fully muscularized diaphragms on D18 in nitrofen-exposed fetuses compared with controls. Similarly, diaphragmatic immunofluorescence of fibrillin-1 was markedly decreased in nitrofen-exposed fetuses compared with controls, which was co-localized with the expression of the mesenchymal marker Gata4.…”

“…Beck et al 13 have reported that cases of CDH and FBN1 gene mutations were associated with sequence changes in the CDH-related gene FRAS1-related extracellular matrix 1 (FREM1). FREM1 encodes an important ECM protein that plays a critical role in the development of multiple organs including the fetal diaphragm.…”

“…12 Recently, mutations in the fibrillin-1 gene (FBN1) have been identified in cases of CDH, thus suggesting that alterations in FBN1 gene expression may lead to diaphragmatic defects. [13][14][15] We designed this study to investigate the hypothesis that the diaphragmatic expression of fibrillin-1 is decreased in the MCT of nitrofen-induced CDH.…”

Whole-genome sequencing of Atacama skeleton shows novel mutations linked with dysplasia

“…In the Ata specimen, we have identified known mutations in genes associated with disease such as cranioectodermal dysplasia (Beck et al 2015) and Greenberg skeletal dysplasia, which each produce phenotypes similar to that observed in the Ata specimen. Ata's genome also contained previously reported variants (rs41298151, p.Gly465Ala) in FREM1 and FLNB (rs1131356, p. Asp1157Asn), which are associated with congenital diaphragmatic hernia (Walczak-Sztulpa et al 2010), a relatively common, lifethreatening birth defect in which the diaphragm does not develop properly (Supplemental Table S6; Stenson et al 2014).…”