title: Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.
abstract: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.
authors.forename: Przemyslaw
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.
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authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.|Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
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authors.affiliation: Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
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authors.affiliation: Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
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authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.|Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
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authors.affiliation: INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain.|CIBERER, ISCIII, Madrid, Spain.
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authors.affiliation: INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain.|CIBERER, ISCIII, Madrid, Spain.
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.|Texas Children's Hospital, Houston, TX, USA.
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authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
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authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.|Texas Children's Hospital, Houston, TX, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
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authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, IL, USA.
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authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
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authors.initials: E
authors.lastname: Popek
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA. pawels@bcm.edu.|Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. pawels@bcm.edu.|Institute of Mother and Child, Warsaw, Poland. pawels@bcm.edu.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D055028:Comparative Genomic Hybridization; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005804:Genes, Lethal; D015894:Genome, Human; D018392:Genomic Imprinting; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D010375:Pedigree; D010547:Persistent Fetal Circulation Syndrome / Q000235:genetics / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000002:abnormalities* / Q000473:pathology; D011667:Pulmonary Veins / Q000473:pathology*; D017384:Sequence Deletion
chemical_list: C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors