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Novel FOXF 1 Deep Intronic Deletion Causes Lethal Lung Developmental Disorder, Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins
Author(s) -
Szafranski Przemyslaw,
Yang Yaping,
Nelson Melissa U.,
Bizzarro Matthew J.,
Morotti Raffaella A.,
Langston Claire,
Stankiewicz Paweł
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22395
Subject(s) - biology , haploinsufficiency , ctcf , genetics , intron , exome sequencing , enhancer , minigene , exome , microbiology and biotechnology , exon , alternative splicing , gene , phenotype , transcription factor
Haploinsufficiency of FOXF 1 causes an autosomal dominant neonatally lethal lung disorder, alveolar capillary dysplasia with misalignment of pulmonary veins ( ACDMPV ). We identified novel 0.8‐kb deletion within the 1.4‐kb intron of FOXF 1 in a deceased newborn diagnosed with ACDMPV . The deletion arose de novo on the maternal copy of the chromosome 16, and did not affect FOXF 1 minigene splicing tested in lung fibroblasts. However, FOXF 1 transcript level in the ACDMPV peripheral lung tissue was reduced by almost 40%. We found that, in an in vitro reporter assay, the FOXF 1 intron exhibited moderate transcriptional enhancer activity, correlating with the presence of binding sites for expression regulators CTCF and CEBPB , whereas its truncated copy, which lost major CTCF and CEBPB ‐binding sites, inhibited the FOXF 1 promoter. Our data further emphasize the importance of testing the non‐protein coding regions of the genome currently not covered by diagnostic chromosomal microarray analyses or whole‐exome sequencing.