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Original article
High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome
  1. Leanne de Kock1,2,
  2. Yu Chang Wang3,
  3. Timothée Revil3,
  4. Dunarel Badescu3,
  5. Barbara Rivera1,2,
  6. Nelly Sabbaghian2,
  7. Mona Wu1,2,
  8. Evan Weber4,
  9. Claudio Sandoval5,
  10. Saskia M J Hopman6,
  11. Johannes H M Merks6,
  12. Johanna M van Hagen7,
  13. Antonia H M Bouts8,
  14. David A Plager9,
  15. Aparna Ramasubramanian9,10,
  16. Linus Forsmark11,
  17. Kristine L Doyle12,
  18. Tonja Toler13,
  19. Janine Callahan14,
  20. Charlotte Engelenberg15,
  21. Dorothée Bouron-Dal Soglio16,
  22. John R Priest17,
  23. Jiannis Ragoussis3,
  24. William D Foulkes1,2,4,18
  1. 1Department of Human Genetics, McGill University, Montréal, Québec, Canada
  2. 2Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, Montréal, Québec, Canada
  3. 3Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montréal, Québec, Canada
  4. 4Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
  5. 5Department of Pediatrics, New York Medical College and Maria Fareri Children's Hospital, Valhalla, New York, USA
  6. 6Department of Pediatric Oncology, Emma Children's Hospital, Academic Medical Center, Amsterdam Zuidoost, The Netherlands
  7. 7Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  8. 8Department of Pediatric Nephrology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands
  9. 9Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA
  10. 10Department of Ophthalmology, University of Louisville, Kentucky, USA
  11. 11Agilent Technologies, Santa Clara, California, USA
  12. 12North Hills, California, USA
  13. 13Petersburg, Indiana, USA
  14. 14Mahopac, New York, USA
  15. 15Amsterdam, The Netherlands
  16. 16Department of Pathology, CHU-Sainte Justine and University of Montreal, Montréal, Québec, Canada
  17. 17Minneapolis, Minnesota, USA
  18. 18Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, Québec, Canada
  1. Correspondence to Dr William D Foulkes, Department of Medical Genetics, Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, Québec, Canada H3T 1E2; william.foulkes{at}


Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous whole-exome sequencing study using DNA derived from peripheral blood identified mosaic mutations in DICER1 in two children with overgrowth and developmental delay as well as more typical phenotypes of germline DICER1 mutation. However, very-low-frequency mosaicism is difficult to detect, and thus, causal mutations can go unnoticed. Highly sensitive, cost-effective approaches are needed to molecularly diagnose these persons. We studied four children with multiple primary tumours known to be associated with the DICER1 syndrome, but in whom germline DICER1 mutations were not detected by conventional mutation detection techniques.

Methods and results We observed the same missense mutation within the DICER1 RNase IIIb domain in multiple tumours from different sites in each patient, raising suspicion of somatic mosaicism. We implemented three different targeted-capture technologies, including the novel HaloPlexHS (Agilent Technologies), followed by deep sequencing, and confirmed that the identified mutations are mosaic in origin in three patients, detectable in 0.24–31% of sequencing reads in constitutional DNA. The mosaic origin of patient 4's mutation remains to be unequivocally established. We also discovered likely pathogenic second somatic mutations or loss of heterozygosity (LOH) in tumours from all four patients.

Conclusions Mosaic DICER1 mutations are an important cause of the DICER1 syndrome in patients with severe phenotypes and often appear to be accompanied by second somatic truncating mutations or LOH in the associated tumours. Furthermore, the molecular barcode-containing HaloPlexHS provides the sensitivity required for detection of such low-level mosaic mutations and could have general applicability.

  • Genetics
  • Molecular genetics
  • Paediatric oncology

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