Narrowing theFOXF1distant enhancer region on 16q24.1 critical for ACDMPV.
Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal lung developmental disorder caused by heterozygous point mutations or genomic deletions involvingFOXF1or its 60-kb tissue-specific enhancer region mapping 270 kb upstream ofFOXF1and involving fetal lung-expressed long non-coding RNA genes and CpG-enriched sites. Recently, we have proposed that theFOXF1locus at 16q24.1 may be a subject of genomic imprinting.



Using custom-designed aCGH and Sanger sequencing, we have identified a novel de novo 104 kb genomic deletion upstream ofFOXF1in a patient with histopathologically verified full phenotype of ACDMPV. This deletion allowed us to further narrow theFOXF1enhancer 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.



Substantial narrowing and bisulfite sequencing of theFOXF1enhancer region on 16q24.1 provided new insights into its regulatory function and genomic imprinting.
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, ABBR R809, Houston, TX 77030 USA.
Przemyslaw
P
Szafranski
Department of Pediatrics, University of New Mexico, Albuquerque, NM USA.
Carmen
C
Herrera
Department of Pathology, University of New Mexico, Albuquerque, NM USA.
Lori A
LA
Proe
Department of Pathology, University of New Mexico, Albuquerque, NM USA.
Brittany
B
Coffman
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX USA.
Debra L
DL
Kearney
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX USA.
Edwina
E
Popek
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, ABBR R809, Houston, TX 77030 USA.
Paweł
0000-0002-6456-7490
P
Stankiewicz
D001665:Binding Sites; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D018899:CpG Islands; D004742:Enhancer Elements, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics*; D050990:GATA3 Transcription Factor / Q000235:genetics; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010547:Persistent Fetal Circulation Syndrome / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D017384:Sequence Deletion; D050986:YY1 Transcription Factor / Q000235:genetics
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D062085:RNA, Long Noncoding; D050986:YY1 Transcription Factor; C494698:YY1 protein, human
Copy-number variants; Genomic imprinting; Transcriptional enhancer