Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a congenital malformation that leads to severe pulmonary hypertension and respiratory failure. It has been associated with deletion of, or mutation in, FOXF1 on 16q24.1, a gene encoding a forkhead transcription factor expressed in the mesenchyme of the developing lung. Here we report on the identification of a pericentric inversion on chromosome 16 (p11.2q24.1) in a case of lethal ACDMPV with atrioventricular septal defect and duodenal atresia. Array-CGH indicated that the inversion is balanced, and FISH showed that the q-arm breakpoint occurs 134 ± 10 kb upstream (5'; centromeric) of FOXF1. This is suggestive of cis-regulatory elements located more than 130 kb 5' of FOXF1, and analysis of genome-wide data sets of chromatin modifications in two different cell types suggested that the FOXF1 regulatory domain covers more than 300 kb, and perhaps up to 433 kb, upstream of the gene, but only 3 kb downstream. The 588 kb gene-free region between FOXF1 and the next gene in the centromeric direction, IRF8, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of FOXF1. Our results further strengthen the association between FOXF1 and a spectrum of malformations that include ACDMPV, atrioventricular septal defects, and gastrointestinal atresia. Furthermore, the presented analysis aids in defining the critical genomic region for this syndrome.

Long noncoding RNAs are spatially correlated with transcription factors and regulate lung development

“…1B). The high enrichment of Fox-binding motifs upstream of lung lncRNA loci suggests regulation by forkhead transcription factors, which are known to regulate foregut development as well as lung endoderm and mesoderm development (Wan et al 2004b;Shu et al 2007;Zhou et al 2008;Chokas et al 2010;Yu et al 2010;Li et al 2012;Parris et al 2013).…”

“…Several lncRNAs are expressed in the lung, including MALAT1, which has been shown to play an important role in lung cancer progression (Schmidt et al 2011;Xu et al 2011;Lai et al 2012). Although loss of MALAT1 does not affect lung development (Zhang et al 2012a), chromosomal deletions encompassing other lncRNAs can cause lethal lung development disorders, suggesting that they may regulate lung development (Stankiewicz et al 2009;Barnett et al 2012;Parris et al 2013;Szafranski et al 2013). Loss of the lncRNA Fendrr has also been shown to result in respiratory defects and perinatal lethality .…”

Genomic and Epigenetic Complexity of the FOXF1 Locus in 16q24.1: Implications for Development and Disease

“…Moreover, it is possible that some patients with ACDMPV that are FOXF1 mutation and deletion negative, may carry submicroscopic retrotransposon ( e.g. LINE-LINE)-mediated balanced paracentric inversions [67, 68] that separate FOXF1 from its long-range upstream regulatory elements [69]. Such rearrangements are challenging for detection using currently available diagnostic technologies.…”

“…Additionally, biallelic expression of Foxf1 has been identified in E15.5 placentas and P21 lungs from reciprocal C57 and PWD strain of mice (unpublished data). The perinatal mortality in Foxf1 +/- mice also does not show a parent-of-origin inheritance pattern when investigated on the CD-1 [69] and C57BL/6J backgrounds (unpublished data). Surviving Foxf1 +/- Swiss Black pups up-regulated the level of Foxf1 to wild type levels and showed only mild abnormalities in alveolar septation without obvious vascular defects [11].…”

Fetal-MRI prenatal diagnosis of severe bilateral lung hypoplasia: alveolar capillary dysplasia case report

“…However, a case of lung hypoplasia have been described in association with a larger chromosomal deletion (about 2,3 Mb) in the same region (patient id 4542 on DECIPHERDatabase of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources; https://deci- , and confirms its non-lymphatic origin (arrow in d). (7,8), in our report, with the aim of implementing US findings, we investigated the prenatal MR characteristics of a diffuse disorder of lung development. In our case prenatal US and MR findings of serious bilateral pulmonary hypoplasia, not associated with other abnormalities (such as congenital diaphragmatic hernia, congenital lung masses, giant omphalocele, severe oligohydramnios and skeletal dysplasia), suggested a diffuse disorder of lung development.…”