Inversion upstream of FOXF1 in a case of lethal alveolar capillary dysplasia with misalignment of pulmonary veins12. Issue 4 (26th February 2013)

• Record Type: Journal Article
• Authors: Parris, Toshima; Nik, Ali Moussavi; Kotecha, Sailesh; Langston, Claire; Helou, Khalil; Platt, Craig; Carlsson, Peter
• Is Part Of: American journal of medical genetics. Volume 161:Issue 4(2013:Apr.)
• Page Start: 764
• Page End: 770
• Publication Date: 2013-02-26
• Subjects: Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.35832
• Languages: English
• ISSNs: 1552-4825

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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, <italic>FOXF1</italic> 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 <italic>FOXF1</italic>. This is suggestive of <italic>cis</italic>‐regulatory elements located more than 130 kb 5′ of <italic>FOXF1</italic>, and analysis of genome‐wide data sets of chromatin modifications in two different cell types suggested that the <italic>FOXF1</italic> 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 <italic>FOXF1</italic> and the next gene in the centromeric direction, <italic>IRF8</italic>, is highly conserved between species and divided into two distinct regulatory domains by an insulator element. Another putative insulator occurs just downstream of <italic>FOXF1</italic>. Our results further strengthen the association between <italic>FOXF1</italic> 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. © 2013 Wiley Periodicals, Inc.</p> </abstract>