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      Pathogenetics of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins

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      Human genetics
      Copy-number variants, genomic imprinting, hypoplastic left heart syndrome and single umbilical artery, transcriptional enhancer, uniparental disomy

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          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 etiology of ACDMPV.

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          Author and article information

          Contributors
          Journal
          7613873
          4137
          Hum Genet
          Hum. Genet.
          Human genetics
          0340-6717
          1432-1203
          18 May 2017
          12 April 2016
          May 2016
          20 July 2017
          : 135
          : 5
          : 569-586
          Affiliations
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
          Genomic Medicine Department, MD Anderson Cancer Center, Houston, TX, USA
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
          Division of Critical Care Medicine, Children’s National Health System, Washington, DC, USA
          Division of Critical Care Medicine, Children’s National Health System, Washington, DC, USA
          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 Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
          Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA
          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, PA, USA
          Department of Pathology, Columbia University Medical Center, New York, NY, USA
          Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
          Children’s Hospital of New York-Presbyterian, New York, NY, USA
          Division of Neonatology, Division of Maternal Fetal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
          Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
          INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain. CIBERER, ISCIII, Madrid, Spain
          INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain. CIBERER, ISCIII, Madrid, Spain
          INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain. CIBERER, ISCIII, Madrid, Spain
          INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain. CIBERER, ISCIII, Madrid, Spain
          Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China. Department of Obstetrics and Gynaecology, and Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China
          Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
          Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
          Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China
          Pediatric Pulmonary Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
          Pediatric Pulmonary Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
          Departments of Pediatrics, University of Alabama at Birmingham, Alabama, USA. Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA
          Department of Surgery, Division of Pediatric Surgery, University of Alabama at Birmingham and Children’s of Alabama, Birmingham, AL, USA
          Department of Pathology, University of Alabama at Birmingham and Pathology and Laboratory Medicine Service, Children’s of Alabama, Birmingham, AL, USA
          Division of Medical Genetics, Department of Pediatrics, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA
          Genetics Department, Kaiser Permanente San Jose Medical Center, San Jose, CA, USA
          Department of Pediatrics, University of Rochester, Rochester, NY, USA
          Division of Neonatology, University of Rochester, Rochester, NY, USA
          Pathology and Laboratory Medicine, Rochester, Rochester, NY, USA
          Department of Medical Genetics, University of British Columbia, Vancouver, Canada
          Department of Medical Genetics, University of British Columbia, Vancouver, Canada
          Department of Medical Genetics, University of British Columbia, Vancouver, Canada
          Department of Medical Genetics, University of British Columbia, Vancouver, Canada
          Department of Pathology, University of British Columbia, Vancouver, Canada
          Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA
          Department of Pathology, Children’s Hospital of San Antonio, San Antonio, TX, USA
          Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA
          Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA
          Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
          Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, SA, Australia
          Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, SA, Australia
          Division of Pediatric Pulmonary Medicine, The Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New York, New York, NY, USA
          Division of Pediatric Pathology, The Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New York, New York, NY, USA
          Division of Medical Genetics, The Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New York, New York, NY, USA
          Pediatric Cardiology, The Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New York, New York, NY, USA
          Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium
          Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium
          Centre for Medical Genetics Ghent, University Hospital Ghent, Ghent, Belgium
          Department of Obstetrics, Gynaecology, and Fertility, AZ St Jan Brugge, Brugge, Begium
          Department of Anatomopathology, AZ St Jan Brugge, Brugge, Begium
          Department of Pathology UZ Leuven, Leuven, Belgium
          Center for Human Genetics, Cliniques Universitaires St-Luc, Universite Catholique de Louvain, Brussels, Belgium
          Division of Pediatric Cardiology, Children’s Mercy Hospital, Kansas City, MS, USA
          Division of Clinical Genetics, Children’s Mercy Hospital, Kansas City, MS, USA
          Division of Paediatric Respiratory & Sleep Medicine, Lady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia. The University of Queensland, Brisbane, QLD, Australia
          Division of Anatomical Pathology, Lady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia. Pathology Queensland, Brisbane, QLD, Australia
          Division of Anatomical Pathology, Lady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia. Pathology Queensland, Brisbane, QLD, Australia
          Clinical Genetics Department, Erasmus MC-Sophia, Rotterdam, Netherlands. Paediatric Surgery, Erasmus MC-Sophia, Rotterdam, Netherlands
          Paediatric Surgery, Erasmus MC-Sophia, Rotterdam, Netherlands
          Clinical Genetics Department, Erasmus MC-Sophia, Rotterdam, Netherlands
          Institut de Pathologie et de Genetique, Gosselies, Belgium
          James Cook University Hospital, Middlesborough, UK
          Department of Paediatric Histopathology, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK
          Clinical Genetics Unit, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK
          Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Sydney, NSW, Australia
          Obstetrics, Gynaecology and Neonatology, Royal Prince Alfred Hospital, Westmead, NSW, Australia
          Obstetrics, Gynaecology and Neonatology, Royal Prince Alfred Hospital, Westmead, NSW, Australia
          Cytogenetics Department, The Children’s Hospital at Westmead, Westmead, NSW, Australia
          Histopathology Department, The Children’s Hospital at Westmead, Westmead, NSW, Australia
          Clinical Genetics Unit, Great Ormond Street Hospital for Children NHS Trust, London, UK
          Department of Histopathology, Addenbrooke’s NHS Trust Pathology Department, Addenbrooke’s Hospital, Cambridge, UK
          Dept of Clinical Genetics, Sheffield Children’s Hospital, Sheffield, UK
          Dept of Clinical Genetics, Sheffield Children’s Hospital, Sheffield, UK
          Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
          Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
          Division of Neonatology, The Children’s Hospital of Philadelphia, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
          Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
          Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
          Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
          Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
          South West Thames Regional Genetics Service, St George’s University Hospital, London, UK
          Critical Care and Cardiorespiratory Unit, Great Ormond Street Hospital NHS Trust, London, UK
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Texas Children’s Hospital, Houston, TX, USA
          Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 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
          Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
          Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA
          Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA
          Author notes
          Correspondence to: Dr. Paweł Stankiewicz, Dept. of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, Texas 77030, USA, Tel: (713) 798-5370, Fax: (713) 798-7418, pawels@ 123456bcm.edu
          Article
          PMC5518754 PMC5518754 5518754 nihpa798882
          10.1007/s00439-016-1655-9
          5518754
          27071622
          b884ffa4-3fcf-40b1-a83e-6c43d9048740
          History
          Categories
          Article

          transcriptional enhancer,Copy-number variants,genomic imprinting,hypoplastic left heart syndrome and single umbilical artery,uniparental disomy

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