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Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

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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 the etiology of ACDMPV.

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Acknowledgements

We are grateful to the ACDMPV families for participation in these studies and the ACD Association for coordination of family recruitments. We thank Drs. K. Aagaard, A.L. Beaudet, J.W. Belmont, A.K. Groves, B. Lee, J.R. Neilson, S.E. Plon, I.B. van den Veyver, and H.Y. Zoghbi for helpful discussion and J.A. Rosenfeld-Mokry for critically reading the manuscript. This work was supported by grants awarded by the US National Heart, Lung, and Blood Institute (NHLBI) grant RO1HL101975 to PSt, NORD grants to PSz, US National Human Genome Research Institute (NHGRI)/NHLBI grant HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and National Institute of Neurological Disorders and Stroke (NINDS) grant NS058529 to JRL.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm. R809, Houston, TX, 77030, USA

    Przemyslaw Szafranski, Tomasz Gambin, Avinash V. Dharmadhikari, Shalini N. Jhangiani, Carlos A. Bacino, James R. Lupski & Paweł Stankiewicz

  2. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA

    Avinash V. Dharmadhikari & Paweł Stankiewicz

  3. Genomic Medicine Department, MD Anderson Cancer Center, Houston, TX, USA

    Kadir Caner Akdemir

  4. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Shalini N. Jhangiani & James R. Lupski

  5. Division of Pediatric Anesthesia and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD, USA

    Jennifer Schuette

  6. Division of Critical Care Medicine, Children’s National Health System, Washington, DC, USA

    Nihal Godiwala

  7. Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, PA, USA

    Svetlana A. Yatsenko & Urvashi Surti

  8. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Svetlana A. Yatsenko & Urvashi Surti

  9. Division of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA

    Jessica Sebastian & Suneeta Madan-Khetarpal

  10. Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA

    Urvashi Surti

  11. Department of Pathology, Columbia University Medical Center, New York, NY, USA

    Rosanna G. Abellar

  12. Department of Pediatrics, Columbia University Medical Center, New York, NY, USA

    David A. Bateman

  13. Children’s Hospital of New York-Presbyterian, New York, NY, USA

    Ashley L. Wilson

  14. Division of Neonatology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA

    Melinda H. Markham

  15. Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA

    Jill Slamon

  16. INGEMM, Instituto de Genética Médica y Molecular, IdiPAZ, Madrid, Spain

    Fernando Santos-Simarro, María Palomares, Julián Nevado & Pablo Lapunzina

  17. CIBERER, ISCIII, Madrid, Spain

    Fernando Santos-Simarro, María Palomares, Julián Nevado & Pablo Lapunzina

  18. Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong, China

    Brian Hon-Yin Chung, Wai-Lap Wong, Yoyo Wing Yiu Chu & Gary Tsz Kin Mok

  19. Department of Obstetrics and Gynaecology, and Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China

    Brian Hon-Yin Chung

  20. Pediatric Pulmonary Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Eitan Kerem & Joel Reiter

  21. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    Namasivayam Ambalavanan

  22. Department of Cell Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA

    Namasivayam Ambalavanan

  23. Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham and Children’s of Alabama, Birmingham, AL, USA

    Scott A. Anderson

  24. Department of Pathology, University of Alabama at Birmingham and Pathology and Laboratory Medicine Service, Children’s of Alabama, Birmingham, AL, USA

    David R. Kelly

  25. Division of Medical Genetics, Department of Pediatrics, and Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA

    Joseph Shieh

  26. Genetics Department, Kaiser Permanente San Jose Medical Center, San Jose, CA, USA

    Taryn C. Rosenthal

  27. Division of Neonatology, Department of Pediatrics, University of Rochester, Rochester, NY, USA

    Kristin Scheible & Laurie Steiner

  28. Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA

    M. Anwar Iqbal

  29. Department of Medical Genetics, University of British Columbia, Vancouver, Canada

    Margaret L. McKinnon, Sara Jane Hamilton, Kamilla Schlade-Bartusiak & Dawn English

  30. Department of Pathology, University of British Columbia, Vancouver, Canada

    Glenda Hendson

  31. Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, USA

    Elizabeth R. Roeder & Rebecca Okashah Littlejohn

  32. Department of Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, USA

    Elizabeth R. Roeder

  33. Department of Pathology, Children’s Hospital of San Antonio, San Antonio, TX, USA

    Thomas S. DeNapoli

  34. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, USA

    Daynna J. Wolff

  35. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA

    Carol L. Wagner

  36. Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Parkville, VIC, Australia

    Alison Yeung & David Francis

  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

    Elizabeth K. Fiorino

  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

    Morris Edelman

  39. Division of Medical Genetics, Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA

    Joyce Fox

  40. Pediatric Cardiology, The Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA

    Denise A. Hayes

  41. Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium

    Sandra Janssens, Elfride De Baere & Björn Menten

  42. Department of Obstetrics, Gynaecology, and Fertility, AZ St Jan Brugge, Brugge, Belgium

    Anne Loccufier

  43. Department of Anatomopathology, AZ St Jan Brugge, Brugge, Belgium

    Lieve Vanwalleghem

  44. Department of Pathology, UZ Leuven, Louvain, Belgium

    Philippe Moerman

  45. Center for Human Genetics, Cliniques Universitaires St-Luc, Universite Catholique de Louvain, Brussels, Belgium

    Yves Sznajer

  46. Division of Pediatric Cardiology, Children’s Mercy Hospital, Kansas City, MS, USA

    Amy S. Lay

  47. Division of Clinical Genetics, Children’s Mercy Hospital, Kansas City, MS, USA

    Jennifer L. Kussmann

  48. Division of Paediatric Respiratory and Sleep Medicine, Lady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia

    Jasneek Chawla

  49. The University of Queensland, Brisbane, QLD, Australia

    Jasneek Chawla

  50. Division of Anatomical Pathology, Lady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health Service, Brisbane, QLD, Australia

    Diane J. Payton & Gael E. Phillips

  51. Pathology Queensland, Brisbane, QLD, Australia

    Diane J. Payton & Gael E. Phillips

  52. Clinical Genetics Department, Erasmus MC-Sophia, Rotterdam, The Netherlands

    Erwin Brosens & Annelies de Klein

  53. Paediatric Surgery, Erasmus MC-Sophia, Rotterdam, The Netherlands

    Erwin Brosens & Dick Tibboel

  54. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium

    Isabelle Maystadt

  55. James Cook University Hospital, Middlesborough, UK

    Richard Fisher

  56. Department of Paediatric Histopathology, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK

    Neil Sebire

  57. Clinical Genetics Unit, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London, UK

    Alison Male & Melissa Lees

  58. Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Maya Chopra & Jason Pinner

  59. Department of Newborn Care, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Girvan Malcolm

  60. Cytogenetics Department, The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Gregory Peters

  61. Histopathology Department, The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Susan Arbuckle

  62. Department of Histopathology, Addenbrooke’s NHS Trust Pathology Department, Addenbrooke’s Hospital, Cambridge, UK

    Zoe Mead

  63. Department of Clinical Genetics, Sheffield Children’s Hospital, Sheffield, UK

    Oliver Quarrell & Richard Sayers

  64. Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK

    Martina Owens & Charles Shaw-Smith

  65. Division of Neonatology, The Children’s Hospital of Philadelphia, The University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA

    Janet Lioy

  66. Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Eileen McKay

  67. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands

    Nicole de Leeuw, Ilse Feenstra & Liesbeth Spruijt

  68. South West Thames Regional Genetics Service, St George’s University Hospital, London, UK

    Frances Elmslie

  69. Critical Care and Cardiorespiratory Unit, Great Ormond Street Hospital NHS Trust, London, UK

    Timothy Thiruchelvam

  70. Texas Children’s Hospital, Houston, TX, USA

    Carlos A. Bacino & James R. Lupski

  71. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    Claire Langston & Edwina Popek

  72. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    James R. Lupski

  73. Department of Pediatrics, Northwestern University, Chicago, IL, USA

    Partha Sen

  74. Institute of Mother and Child, Warsaw, Poland

    Paweł Stankiewicz

Authors
  1. Przemyslaw Szafranski
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Corresponding author

Correspondence to Paweł Stankiewicz.

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Szafranski, P., Gambin, T., Dharmadhikari, A.V. et al. Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet 135, 569–586 (2016). https://doi.org/10.1007/s00439-016-1655-9

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  • DOI: https://doi.org/10.1007/s00439-016-1655-9

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