Abstract
BACKGROUND: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder caused by heterozygous point mutations or genomic deletions involving FOXF1 or its 60-kb tissue-specific enhancer region mapping 270 kb upstream of FOXF1 and involving fetal lung-expressed long non-coding RNA genes and CpG-enriched sites. Recently, we have proposed that the FOXF1 locus at 16q24.1 may be a subject of genomic imprinting. FINDINGS: Using custom-designed aCGH and Sanger sequencing, we have identified a novel de novo 104 kb genomic deletion upstream of FOXF1 in a patient with histopathologically verified full phenotype of ACDMPV. This deletion allowed us to further narrow the FOXF1 enhancer region and identify its critical 15-kb core interval, essential for lung development. This interval harbors binding sites for lung-expressed transcription factors, including GATA3, ESR1, and YY1, and is flanked by the lncRNA genes and CpG islands. Bisulfite sequencing of one of these CpG islands on the non-deleted allele showed that it is predominantly methylated on the maternal chromosome 16. CONCLUSIONS: Substantial narrowing and bisulfite sequencing of the FOXF1 enhancer region on 16q24.1 provided new insights into its regulatory function and genomic imprinting.