FOXF1 – Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, neonatally lethal lung developmental disorder characterized by severe respiratory distress, persistent pulmonary hypertension, and refractory hypoxemia unresponsive to therapy. Affected infants uniformly die within the first month of life without lung transplant ([PMID:19500772]).

Heterozygous FOXF1 variants cause ACD/MPV in an autosomal dominant manner with evidence of paternal imprinting. Over 90 unrelated probands harbor de novo nonsense, frameshift, missense, no-stop, and enhancer copy‐number variants in FOXF1 ([PMID:23505205]), and familial segregation in four pedigrees—including one with five of six siblings affected—confirms transmission and imprinting effects ([PMID:22990143]).

The variant spectrum includes 38 novel nonsynonymous changes: nine nonsense, seven frameshift, one in‐frame deletion, 20 missense, and one no-stop mutation; recurrent hotspot c.691_698del (p.Ala231ArgfsTer61) has been reported in three unrelated families ([PMID:23505205]; [PMID:31436901]). Deep intronic deletions and enhancer CNVs reduce FOXF1 transcript levels by ~40% and disrupt enhancer activity in lung fibroblasts ([PMID:23943206]).

Functional studies demonstrate that FOXF1 haploinsufficiency impairs vascular development via loss of endothelial FOXF1. Endothelial‐specific Foxf1 knockout mice recapitulate ACD/MPV features, showing reduced proliferation, increased apoptosis, and downregulation of VEGF receptors FLT1/FLK1, PECAM1, PDGFB, and integrin β3 ([PMID:25091710]). The S52F FOXF1 mutation disrupts STAT3 binding, inhibits angiogenic signaling, and nanoparticle delivery of STAT3 cDNA rescues lung angiogenesis in knock‐in mice ([PMID:31199666]).

Non‐coding SNVs in the lung‐specific FOXF1 enhancer can mitigate or rescue the ACD/MPV phenotype by acting as hypermorphs or by modifying allele‐specific expression; a regulatory SNV rs560517434-A increased promoter activity 10‐fold in vitro and correlates with survival in a four‐generation family ([PMID:35902696]). Deep parental mosaicism for enhancer deletions underscores variable penetrance and high recurrence risk ([PMID:36124617]).

No studies to date have refuted the FOXF1–ACD/MPV association. The weight of genetic and experimental evidence meets ClinGen criteria for a definitive gene–disease relationship, supporting rapid, noninvasive FOXF1 testing in neonates with unexplained pulmonary hypertension.

Key Take-home: Early FOXF1 sequencing enables prompt diagnosis of ACD/MPV, informs prognostication, and guides clinical decision-making in critically ill neonates.

References

• American journal of human genetics • 2009 • Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations PMID:19500772
• Human mutation • 2013 • Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain PMID:23505205
• Neonatology • 2013 • A novel mutation in FOXF1 gene associated with alveolar capillary dysplasia with misalignment of pulmonary veins, intestinal malrotation and annular pancreas PMID:23407133
• Human mutation • 2013 • Novel FOXF1 deep intronic deletion causes lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins PMID:23943206
• Circulation research • 2014 • FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells PMID:25091710
• American journal of respiratory and critical care medicine • 2019 • The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia PMID:31199666
• American journal of medical genetics. Part A • 2019 • A recurrent 8 bp frameshifting indel in FOXF1 defines a novel mutation hotspot associated with alveolar capillary dysplasia with misalignment of pulmonary veins PMID:31436901
• European journal of human genetics • 2022 • Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant PMID:35902696
• Molecular genetics & genomic medicine • 2022 • High-level gonosomal mosaicism for a pathogenic non-coding CNV deletion of the lung-specific FOXF1 enhancer in an unaffected mother of an infant with ACDMPV PMID:36124617

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