Prenatal Rare 16q24.1 Deletion Between Genomics and Epigenetics: A Review

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare, often fatal congenital disorder characterized by severe neonatal respiratory distress and associated with complex multisystem malformations. In approximately 90% of cases, the condition is linked to deletions or mutations affecting the FOXF1 gene or its upstream enhancer region on chromosome 16q24.1. This review analyzes reported prenatal cases with 16q24.1 deletion involving FOXF1, aiming to identify recurrent sonographic features and elucidate the underlying genomic and epigenetic mechanisms. We reviewed prenatal cases reported in the literature involving deletions of the 16q24.1 region, including the FOXF1 gene. Here, we expand the case series by reporting a fetus with increased nuchal translucency measuring 8 mm and a de novo 16q24.1 deletion. We identified nine prenatal cases with a 16q24.1 deletion, all involving the FOXF1 gene or its enhancer region. The main ultrasound findings included increased nuchal translucency and cystic hygroma during the first trimester, and cardiac, renal, and intestinal malformations from 20 weeks of gestation onward. Prenatal diagnosis of ACDMPV based solely on ultrasound findings is challenging. In most reported cases, the pregnancy was carried to term, with the diagnosis being confirmed by post-mortem histopathological examination. In the only case in which the pregnancy was terminated at 14 weeks' gestation, histological examination of the fetal lungs, despite them being in the early stages of development, revealed misaligned pulmonary veins in close proximity to the pulmonary arteries and bronchioles. Evidence highlights the significance of non-coding regulatory regions in the regulation of FOXF1 expression. Differential methylation patterns, and possible contributions of parental imprinting, highlight the complexity of FOXF1 regulation. Early detection through array comparative genomic hybridization (array CGH) or next-generation sequencing to identify point mutations in the FOXF1 gene, combined with increased awareness of ultrasound markers suggestive of the condition, could improve the accuracy of prenatal diagnosis and genetic counseling. Further research into the epigenetic regulation of FOXF1 is crucial for refining recurrence risk estimates and improving genetic counseling practices.