Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in etiology of ACDMPV.

Narrowing the FOXF1 distant enhancer region on 16q24.1 critical for ACDMPV

“…Patients with ACDMPV present with respiratory distress usually accompanied by pulmonary hypertension and often by extra-pulmonary anomalies [3, 4]. …”

“…In the vast majority of patients with ACDMPV, heterozygous de novo point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its distant enhancer region on chromosome 16q24.1 have been identified [4–7]. FOXF1 is a transcription factor involved, among others, in maintaining the endothelial barrier through activation of the S1P/S1PR1 signaling required for the integrity of adherens junctions [8].…”

“…This region encodes fetal lung-expressed long non-coding RNAs, LINC01081 and LINC01082 , and encompasses binding sites for numerous transcriptional regulators, including CEBP/p300, CTCF, and GLI2 [4, 7]. Both LINC01081 and GLI2 have been shown to positively control FOXF1 expression in human fetal lung fibroblasts [7, 9].…”

“…Recently, in vivo studies of the mouse syntenic region have shown that it likewise harbors a Foxf1 enhancer [10]. Of note, 30 of 31 genomic deletions pathogenic for ACDMPV, for which parental origin was determined, occurred de novo on the maternal chromosome 16, suggesting genomic imprinting of the FOXF1 locus [4]. Importantly, some of the GLI2-binding sites located in the enhancer region have been found to reside in a partially methylated CpG island, and their function has been shown to be methylation sensitive [7].…”

Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith–Magenis syndrome with evident peripheral neuropathy

“…DNA rearrangements have been demonstrated to cause gene interruption or fusion by disrupting gene structure, altering the copy number of dosage-sensitive gene(s), or imposing a position effect on the regulation of gene expression; the latter is potentially mediated through altering Topologically Associating Domains (TAD) or effecting long noncoding RNA (lncRNA) (Lupianez et al 2015; Szafranski et al 2016). Deletion of a genomic segment may unmask recessive mutation(s) on the other allele (Liburd et al 2001; Wu et al 2015).…”