Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder

  1. Paweł Stankiewicz1,2,23
  1. 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA;
  2. 2Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas 77030, USA;
  3. 3Clinical Genetics Department, Erasmus MC-Sophia, 3000 CA, Rotterdam, Netherlands;
  4. 4Paediatric Surgery, Erasmus MC-Sophia, 3015 GJ, Rotterdam, Netherlands;
  5. 5Center for Cardiovascular Genetics, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center and Texas Heart Institute, Houston, Texas 77030, USA;
  6. 6Institute of Informatics, University of Warsaw, 02-097, Warsaw, Poland;
  7. 7College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, 02-089, Warsaw, Poland;
  8. 8Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;
  9. 9Department of Biological Sciences, Birla Institute of Technology and Science-Pilani, Hyderabad-500 078, AP, India;
  10. 10Department of Molecular and Clinical Genetics, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia;
  11. 11Obstetrics, Gynaecology and Neonatology, Royal Prince Alfred Hospital, Sydney, NSW 2006, Australia;
  12. 12Cytogenetics Department, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia;
  13. 13Histopathology Department, The Children's Hospital at Westmead, Westmead, NSW 2145, Australia;
  14. 14Department of Pediatrics–Neonatology, University of Minnesota Medical Center, Minneapolis, Minnesota 55454, USA;
  15. 15Minnesota Neonatal Physicians, Minneapolis, Minnesota 55404, USA;
  16. 16Laboratory Medicine and Pathology, Department of Medicine, University of Minnesota Medical Center, Minneapolis, Minnesota 55454, USA;
  17. 17Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA;
  18. 18Institut de Pathologie et de Génétique, B-6041 Gosselies, Belgium;
  19. 19Department of Paediatric Histopathology, Great Ormond Street Hospital for Children and UCL Institute of Child Health, London WC1N 3JH, United Kingdom;
  20. 20James Cook University Hospital, Middlesborough TS4 3BW, United Kingdom;
  21. 21Department of Pathology, Baylor College of Medicine, and Pulmonary Pathology, Texas Children's Hospital, Houston, Texas 77030, USA;
  22. 22Department of Pediatrics–Neonatology, Baylor College of Medicine, Houston, Texas 77030, USA

    Abstract

    An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

    Footnotes

    • Received April 16, 2012.
    • Accepted September 17, 2012.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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    1. Published in Advance October 3, 2012, doi: 10.1101/gr.141887.112 Genome Res. 23: 23-33 © 2013, Published by Cold Spring Harbor Laboratory Press

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