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Hum Genet. 2016 May;135(5):569-86. doi: 10.1007/s00439-016-1655-9. Epub 2016 Apr 12.

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins.

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA.
2
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
3
Genomic Medicine Department, MD Anderson Cancer Center, Houston, TX, USA.
4
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
5
Division of Pediatric Anesthesia and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
6
Division of Critical Care Medicine, Children's National Health System, Washington, DC, USA.
7
Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA.
8
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
9
Division of Medical Genetics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA.
10
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
11
Department of Pathology, Columbia University Medical Center, New York, NY, USA.
12
Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
13
Children's Hospital of New York-Presbyterian, New York, NY, USA.
14
Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
15
Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
16
INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain.
17
CIBERER, ISCIII, Madrid, Spain.
18
Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China.
19
Department of Obstetrics and Gynaecology, and Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China.
20
Pediatric Pulmonary Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
21
Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA.
22
Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
23
Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham and Children's of Alabama, Birmingham, AL, USA.
24
Department of Pathology, University of Alabama at Birmingham and Pathology and Laboratory Medicine Service, Children's of Alabama, Birmingham, AL, USA.
25
Division of Medical Genetics, Department of Pediatrics, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
26
Genetics Department, Kaiser Permanente San Jose Medical Center, San Jose, CA, USA.
27
Division of Neonatology, Department of Pediatrics, University of Rochester, Rochester, NY, USA.
28
Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
29
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
30
Department of Pathology, University of British Columbia, Vancouver, Canada.
31
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA.
32
Department of Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA.
33
Department of Pathology, Children's Hospital of San Antonio, San Antonio, TX, USA.
34
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA.
35
Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA.
36
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, VIC, Australia.
37
Division of Pediatric Pulmonary Medicine, The Children's Heart Center Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
38
Division of Pediatric Pathology, The Children's Heart Center Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
39
Division of Medical Genetics, Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
40
Pediatric Cardiology, The Children's Heart Center Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA.
41
Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
42
Department of Obstetrics, Gynaecology, and Fertility, AZ St Jan Brugge, Brugge, Belgium.
43
Department of Anatomopathology, AZ St Jan Brugge, Brugge, Belgium.
44
Department of Pathology, UZ Leuven, Louvain, Belgium.
45
Center for Human Genetics, Cliniques Universitaires St-Luc, Universite Catholique de Louvain, Brussels, Belgium.
46
Division of Pediatric Cardiology, Children's Mercy Hospital, Kansas City, MS, USA.
47
Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MS, USA.
48
Division of Paediatric Respiratory and Sleep Medicine, Lady Cilento Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia.
49
The University of Queensland, Brisbane, QLD, Australia.
50
Division of Anatomical Pathology, Lady Cilento Children's Hospital, Children's Health Queensland Hospital and Health Service, Brisbane, QLD, Australia.
51
Pathology Queensland, Brisbane, QLD, Australia.
52
Clinical Genetics Department, Erasmus MC-Sophia, Rotterdam, The Netherlands.
53
Paediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands.
54
Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium.
55
James Cook University Hospital, Middlesborough, UK.
56
Department of Paediatric Histopathology, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK.
57
Clinical Genetics Unit, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK.
58
Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
59
Department of Newborn Care, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
60
Cytogenetics Department, The Children's Hospital at Westmead, Westmead, NSW, Australia.
61
Histopathology Department, The Children's Hospital at Westmead, Westmead, NSW, Australia.
62
Department of Histopathology, Addenbrooke's NHS Trust Pathology Department, Addenbrooke's Hospital, Cambridge, UK.
63
Department of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK.
64
Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
65
Division of Neonatology, The Children's Hospital of Philadelphia, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
66
Department of Pathology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
67
Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
68
South West Thames Regional Genetics Service, St George's University Hospital, London, UK.
69
Critical Care and Cardiorespiratory Unit, Great Ormond Street Hospital NHS Trust, London, UK.
70
Texas Children's Hospital, Houston, TX, USA.
71
Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA.
72
Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
73
Department of Pediatrics, Northwestern University, Chicago, IL, USA.
74
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA. pawels@bcm.edu.
75
Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. pawels@bcm.edu.
76
Institute of Mother and Child, Warsaw, Poland. pawels@bcm.edu.

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.

PMID:
27071622
PMCID:
PMC5518754
DOI:
10.1007/s00439-016-1655-9
[Indexed for MEDLINE]
Free PMC Article

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