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Human Genetics

, Volume 135, Issue 5, pp 569–586 | Cite as

Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins

  • Przemyslaw Szafranski
  • Tomasz Gambin
  • Avinash V. Dharmadhikari
  • Kadir Caner Akdemir
  • Shalini N. Jhangiani
  • Jennifer Schuette
  • Nihal Godiwala
  • Svetlana A. Yatsenko
  • Jessica Sebastian
  • Suneeta Madan-Khetarpal
  • Urvashi Surti
  • Rosanna G. Abellar
  • David A. Bateman
  • Ashley L. Wilson
  • Melinda H. Markham
  • Jill Slamon
  • Fernando Santos-Simarro
  • María Palomares
  • Julián Nevado
  • Pablo Lapunzina
  • Brian Hon-Yin Chung
  • Wai-Lap Wong
  • Yoyo Wing Yiu Chu
  • Gary Tsz Kin Mok
  • Eitan Kerem
  • Joel Reiter
  • Namasivayam Ambalavanan
  • Scott A. Anderson
  • David R. Kelly
  • Joseph Shieh
  • Taryn C. Rosenthal
  • Kristin Scheible
  • Laurie Steiner
  • M. Anwar Iqbal
  • Margaret L. McKinnon
  • Sara Jane Hamilton
  • Kamilla Schlade-Bartusiak
  • Dawn English
  • Glenda Hendson
  • Elizabeth R. Roeder
  • Thomas S. DeNapoli
  • Rebecca Okashah Littlejohn
  • Daynna J. Wolff
  • Carol L. Wagner
  • Alison Yeung
  • David Francis
  • Elizabeth K. Fiorino
  • Morris Edelman
  • Joyce Fox
  • Denise A. Hayes
  • Sandra Janssens
  • Elfride De Baere
  • Björn Menten
  • Anne Loccufier
  • Lieve Vanwalleghem
  • Philippe Moerman
  • Yves Sznajer
  • Amy S. Lay
  • Jennifer L. Kussmann
  • Jasneek Chawla
  • Diane J. Payton
  • Gael E. Phillips
  • Erwin Brosens
  • Dick Tibboel
  • Annelies de Klein
  • Isabelle Maystadt
  • Richard Fisher
  • Neil Sebire
  • Alison Male
  • Maya Chopra
  • Jason Pinner
  • Girvan Malcolm
  • Gregory Peters
  • Susan Arbuckle
  • Melissa Lees
  • Zoe Mead
  • Oliver Quarrell
  • Richard Sayers
  • Martina Owens
  • Charles Shaw-Smith
  • Janet Lioy
  • Eileen McKay
  • Nicole de Leeuw
  • Ilse Feenstra
  • Liesbeth Spruijt
  • Frances Elmslie
  • Timothy Thiruchelvam
  • Carlos A. Bacino
  • Claire Langston
  • James R. Lupski
  • Partha Sen
  • Edwina Popek
  • Paweł StankiewiczEmail author
Original Investigation

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.

Keywords

Hypoplastic Left Heart Syndrome Whole Exome Sequencing Upstream Regulatory Region Paternal Chromosome Maternal Chromosome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Compliance with ethical standards

Conflict of interest

No competing interest is declared.

Supplementary material

439_2016_1655_MOESM1_ESM.docx (2.4 mb)
Supplementary material 1 (DOCX 2499 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Przemyslaw Szafranski
    • 1
  • Tomasz Gambin
    • 1
  • Avinash V. Dharmadhikari
    • 1
    • 2
  • Kadir Caner Akdemir
    • 3
  • Shalini N. Jhangiani
    • 1
    • 4
  • Jennifer Schuette
    • 5
  • Nihal Godiwala
    • 6
  • Svetlana A. Yatsenko
    • 7
    • 8
  • Jessica Sebastian
    • 9
  • Suneeta Madan-Khetarpal
    • 9
  • Urvashi Surti
    • 7
    • 8
    • 10
  • Rosanna G. Abellar
    • 11
  • David A. Bateman
    • 12
  • Ashley L. Wilson
    • 13
  • Melinda H. Markham
    • 14
  • Jill Slamon
    • 15
  • Fernando Santos-Simarro
    • 16
    • 17
  • María Palomares
    • 16
    • 17
  • Julián Nevado
    • 16
    • 17
  • Pablo Lapunzina
    • 16
    • 17
  • Brian Hon-Yin Chung
    • 18
    • 19
  • Wai-Lap Wong
    • 18
  • Yoyo Wing Yiu Chu
    • 18
  • Gary Tsz Kin Mok
    • 18
  • Eitan Kerem
    • 20
  • Joel Reiter
    • 20
  • Namasivayam Ambalavanan
    • 21
    • 22
  • Scott A. Anderson
    • 23
  • David R. Kelly
    • 24
  • Joseph Shieh
    • 25
  • Taryn C. Rosenthal
    • 26
  • Kristin Scheible
    • 27
  • Laurie Steiner
    • 27
  • M. Anwar Iqbal
    • 28
  • Margaret L. McKinnon
    • 29
  • Sara Jane Hamilton
    • 29
  • Kamilla Schlade-Bartusiak
    • 29
  • Dawn English
    • 29
  • Glenda Hendson
    • 30
  • Elizabeth R. Roeder
    • 31
    • 32
  • Thomas S. DeNapoli
    • 33
  • Rebecca Okashah Littlejohn
    • 31
  • Daynna J. Wolff
    • 34
  • Carol L. Wagner
    • 35
  • Alison Yeung
    • 36
  • David Francis
    • 36
  • Elizabeth K. Fiorino
    • 37
  • Morris Edelman
    • 38
  • Joyce Fox
    • 39
  • Denise A. Hayes
    • 40
  • Sandra Janssens
    • 41
  • Elfride De Baere
    • 41
  • Björn Menten
    • 41
  • Anne Loccufier
    • 42
  • Lieve Vanwalleghem
    • 43
  • Philippe Moerman
    • 44
  • Yves Sznajer
    • 45
  • Amy S. Lay
    • 46
  • Jennifer L. Kussmann
    • 47
  • Jasneek Chawla
    • 48
    • 49
  • Diane J. Payton
    • 50
    • 51
  • Gael E. Phillips
    • 50
    • 51
  • Erwin Brosens
    • 52
    • 53
  • Dick Tibboel
    • 53
  • Annelies de Klein
    • 52
  • Isabelle Maystadt
    • 54
  • Richard Fisher
    • 55
  • Neil Sebire
    • 56
  • Alison Male
    • 57
  • Maya Chopra
    • 58
  • Jason Pinner
    • 58
  • Girvan Malcolm
    • 59
  • Gregory Peters
    • 60
  • Susan Arbuckle
    • 61
  • Melissa Lees
    • 57
  • Zoe Mead
    • 62
  • Oliver Quarrell
    • 63
  • Richard Sayers
    • 63
  • Martina Owens
    • 64
  • Charles Shaw-Smith
    • 64
  • Janet Lioy
    • 65
  • Eileen McKay
    • 66
  • Nicole de Leeuw
    • 67
  • Ilse Feenstra
    • 67
  • Liesbeth Spruijt
    • 67
  • Frances Elmslie
    • 68
  • Timothy Thiruchelvam
    • 69
  • Carlos A. Bacino
    • 1
    • 70
  • Claire Langston
    • 71
  • James R. Lupski
    • 1
    • 4
    • 70
    • 72
  • Partha Sen
    • 73
  • Edwina Popek
    • 71
  • Paweł Stankiewicz
    • 1
    • 2
    • 74
    Email author
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Interdepartmental Program in Translational Biology and Molecular MedicineBaylor College of MedicineHoustonUSA
  3. 3.Genomic Medicine DepartmentMD Anderson Cancer CenterHoustonUSA
  4. 4.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  5. 5.Division of Pediatric Anesthesia and Critical Care MedicineJohns Hopkins Medical InstitutionsBaltimoreUSA
  6. 6.Division of Critical Care MedicineChildren’s National Health SystemWashington, DCUSA
  7. 7.Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Medical Genetics and GenomicsMagee-Womens Hospital of UPMCPittsburghUSA
  8. 8.Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  9. 9.Division of Medical GeneticsChildren’s Hospital of Pittsburgh of UPMCPittsburghUSA
  10. 10.Department of Human Genetics, Graduate School of Public HealthUniversity of PittsburghPittsburghUSA
  11. 11.Department of PathologyColumbia University Medical CenterNew YorkUSA
  12. 12.Department of PediatricsColumbia University Medical CenterNew YorkUSA
  13. 13.Children’s Hospital of New York-PresbyterianNew YorkUSA
  14. 14.Division of Neonatology, Department of PediatricsVanderbilt University Medical CenterNashvilleUSA
  15. 15.Division of Maternal Fetal Medicine, Department of Obstetrics and GynecologyVanderbilt University Medical CenterNashvilleUSA
  16. 16.INGEMM, Instituto de Genética Médica y Molecular, IdiPAZMadridSpain
  17. 17.CIBERER, ISCIIIMadridSpain
  18. 18.Department of Paediatrics and Adolescent MedicineThe University of Hong KongHong KongChina
  19. 19.Department of Obstetrics and Gynaecology, and Centre for Genomic SciencesThe University of Hong KongHong KongChina
  20. 20.Pediatric Pulmonary Unit, Department of PediatricsHadassah-Hebrew University Medical CenterJerusalemIsrael
  21. 21.Department of PediatricsUniversity of Alabama at BirminghamBirminghamUSA
  22. 22.Department of Cell Developmental and Integrative BiologyUniversity of Alabama at BirminghamBirminghamUSA
  23. 23.Division of Pediatric Surgery, Department of SurgeryUniversity of Alabama at Birmingham and Children’s of AlabamaBirminghamUSA
  24. 24.Department of PathologyUniversity of Alabama at Birmingham and Pathology and Laboratory Medicine Service, Children’s of AlabamaBirminghamUSA
  25. 25.Division of Medical Genetics, Department of Pediatrics, and Institute for Human GeneticsUniversity of California San FranciscoSan FranciscoUSA
  26. 26.Genetics DepartmentKaiser Permanente San Jose Medical CenterSan JoseUSA
  27. 27.Division of Neonatology, Department of PediatricsUniversity of RochesterRochesterUSA
  28. 28.Pathology and Laboratory MedicineUniversity of Rochester Medical CenterRochesterUSA
  29. 29.Department of Medical GeneticsUniversity of British ColumbiaVancouverCanada
  30. 30.Department of PathologyUniversity of British ColumbiaVancouverCanada
  31. 31.Department of PediatricsBaylor College of MedicineSan AntonioUSA
  32. 32.Department of Molecular and Human GeneticsBaylor College of MedicineSan AntonioUSA
  33. 33.Department of PathologyChildren’s Hospital of San AntonioSan AntonioUSA
  34. 34.Department of Pathology and Laboratory MedicineMedical University of South CarolinaCharlestonUSA
  35. 35.Department of PediatricsMedical University of South CarolinaCharlestonUSA
  36. 36.Victorian Clinical Genetics ServicesMurdoch Childrens Research InstituteParkvilleAustralia
  37. 37.Division of Pediatric Pulmonary MedicineThe Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New YorkNew Hyde ParkUSA
  38. 38.Division of Pediatric PathologyThe Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New YorkNew Hyde ParkUSA
  39. 39.Division of Medical GeneticsSteven and Alexandra Cohen Children’s Medical Center of New YorkNew Hyde ParkUSA
  40. 40.Pediatric CardiologyThe Children’s Heart Center Steven and Alexandra Cohen Children’s Medical Center of New YorkNew Hyde ParkUSA
  41. 41.Center for Medical GeneticsGhent University and Ghent University HospitalGhentBelgium
  42. 42.Department of Obstetrics, Gynaecology, and FertilityAZ St Jan BruggeBruggeBelgium
  43. 43.Department of AnatomopathologyAZ St Jan BruggeBruggeBelgium
  44. 44.Department of PathologyUZ LeuvenLouvainBelgium
  45. 45.Center for Human Genetics, Cliniques Universitaires St-LucUniversite Catholique de LouvainBrusselsBelgium
  46. 46.Division of Pediatric CardiologyChildren’s Mercy HospitalKansas CityUSA
  47. 47.Division of Clinical GeneticsChildren’s Mercy HospitalKansas CityUSA
  48. 48.Division of Paediatric Respiratory and Sleep MedicineLady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health ServiceBrisbaneAustralia
  49. 49.The University of QueenslandBrisbaneAustralia
  50. 50.Division of Anatomical PathologyLady Cilento Children’s Hospital, Children’s Health Queensland Hospital and Health ServiceBrisbaneAustralia
  51. 51.Pathology QueenslandBrisbaneAustralia
  52. 52.Clinical Genetics DepartmentErasmus MC-SophiaRotterdamThe Netherlands
  53. 53.Paediatric SurgeryErasmus MC-SophiaRotterdamThe Netherlands
  54. 54.Centre de Génétique HumaineInstitut de Pathologie et de GénétiqueGosseliesBelgium
  55. 55.James Cook University HospitalMiddlesboroughUK
  56. 56.Department of Paediatric HistopathologyGreat Ormond Street Hospital for Children and UCL Institute of Child HealthLondonUK
  57. 57.Clinical Genetics UnitGreat Ormond Street Hospital for Children and UCL Institute of Child HealthLondonUK
  58. 58.Department of Medical GenomicsRoyal Prince Alfred HospitalSydneyAustralia
  59. 59.Department of Newborn CareRoyal Prince Alfred HospitalSydneyAustralia
  60. 60.Cytogenetics DepartmentThe Children’s Hospital at WestmeadWestmeadAustralia
  61. 61.Histopathology DepartmentThe Children’s Hospital at WestmeadWestmeadAustralia
  62. 62.Department of HistopathologyAddenbrooke’s NHS Trust Pathology Department, Addenbrooke’s HospitalCambridgeUK
  63. 63.Department of Clinical GeneticsSheffield Children’s HospitalSheffieldUK
  64. 64.Molecular Genetics DepartmentRoyal Devon and Exeter NHS Foundation TrustExeterUK
  65. 65.Division of Neonatology, The Children’s Hospital of PhiladelphiaThe University of Pennsylvania, Perelman School of MedicinePhiladelphiaUSA
  66. 66.Department of PathologyThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  67. 67.Department of Human GeneticsRadboud University Medical CenterNijmegenThe Netherlands
  68. 68.South West Thames Regional Genetics ServiceSt George’s University HospitalLondonUK
  69. 69.Critical Care and Cardiorespiratory UnitGreat Ormond Street Hospital NHS TrustLondonUK
  70. 70.Texas Children’s HospitalHoustonUSA
  71. 71.Department of Pathology and ImmunologyBaylor College of MedicineHoustonUSA
  72. 72.Department of PediatricsBaylor College of MedicineHoustonUSA
  73. 73.Department of PediatricsNorthwestern UniversityChicagoUSA
  74. 74.Institute of Mother and ChildWarsawPoland

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