High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

Leanne de Kock, Yu Chang Wang, Timothée Revil, Dunarel Badescu, Barbara Rivera, Nelly Sabbaghian, Mona Wu, Evan Weber, Claudio Sandoval, Saskia M J Hopman, Johannes H M Merks, Johanna M. van Hagen, Antonia H M Bouts, David Plager, Aparna Ramasubramanian, Linus Forsmark, Kristine L. Doyle, Tonja Toler, Janine Callahan, Charlotte Engelenberg & 4 others Dorothée Bouron Dal Soglio, John R. Priest, Jiannis Ragoussis, William D. Foulkes

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous wholeexome 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, costeffective 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.

Original languageEnglish (US)
Pages (from-to)43-52
Number of pages10
JournalJournal of Medical Genetics
Volume53
Issue number1
DOIs
StatePublished - 2016

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Mosaicism
Mutation
Germ-Line Mutation
Loss of Heterozygosity
Neoplasms
Technology
Phenotype
High-Throughput Nucleotide Sequencing
DNA
Missense Mutation
Ribonucleases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

de Kock, L., Wang, Y. C., Revil, T., Badescu, D., Rivera, B., Sabbaghian, N., ... Foulkes, W. D. (2016). High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome. Journal of Medical Genetics, 53(1), 43-52. https://doi.org/10.1136/jmedgenet-2015-103428

High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome. / de Kock, Leanne; Wang, Yu Chang; Revil, Timothée; Badescu, Dunarel; Rivera, Barbara; Sabbaghian, Nelly; Wu, Mona; Weber, Evan; Sandoval, Claudio; Hopman, Saskia M J; Merks, Johannes H M; van Hagen, Johanna M.; Bouts, Antonia H M; Plager, David; Ramasubramanian, Aparna; Forsmark, Linus; Doyle, Kristine L.; Toler, Tonja; Callahan, Janine; Engelenberg, Charlotte; Soglio, Dorothée Bouron Dal; Priest, John R.; Ragoussis, Jiannis; Foulkes, William D.

In: Journal of Medical Genetics, Vol. 53, No. 1, 2016, p. 43-52.

Research output: Contribution to journalArticle

de Kock, L, Wang, YC, Revil, T, Badescu, D, Rivera, B, Sabbaghian, N, Wu, M, Weber, E, Sandoval, C, Hopman, SMJ, Merks, JHM, van Hagen, JM, Bouts, AHM, Plager, D, Ramasubramanian, A, Forsmark, L, Doyle, KL, Toler, T, Callahan, J, Engelenberg, C, Soglio, DBD, Priest, JR, Ragoussis, J & Foulkes, WD 2016, 'High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome', Journal of Medical Genetics, vol. 53, no. 1, pp. 43-52. https://doi.org/10.1136/jmedgenet-2015-103428
de Kock, Leanne ; Wang, Yu Chang ; Revil, Timothée ; Badescu, Dunarel ; Rivera, Barbara ; Sabbaghian, Nelly ; Wu, Mona ; Weber, Evan ; Sandoval, Claudio ; Hopman, Saskia M J ; Merks, Johannes H M ; van Hagen, Johanna M. ; Bouts, Antonia H M ; Plager, David ; Ramasubramanian, Aparna ; Forsmark, Linus ; Doyle, Kristine L. ; Toler, Tonja ; Callahan, Janine ; Engelenberg, Charlotte ; Soglio, Dorothée Bouron Dal ; Priest, John R. ; Ragoussis, Jiannis ; Foulkes, William D. / High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome. In: Journal of Medical Genetics. 2016 ; Vol. 53, No. 1. pp. 43-52.
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abstract = "Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous wholeexome 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, costeffective 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.",
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T1 - High-sensitivity sequencing reveals multi-organ somatic mosaicism causing DICER1 syndrome

AU - de Kock, Leanne

AU - Wang, Yu Chang

AU - Revil, Timothée

AU - Badescu, Dunarel

AU - Rivera, Barbara

AU - Sabbaghian, Nelly

AU - Wu, Mona

AU - Weber, Evan

AU - Sandoval, Claudio

AU - Hopman, Saskia M J

AU - Merks, Johannes H M

AU - van Hagen, Johanna M.

AU - Bouts, Antonia H M

AU - Plager, David

AU - Ramasubramanian, Aparna

AU - Forsmark, Linus

AU - Doyle, Kristine L.

AU - Toler, Tonja

AU - Callahan, Janine

AU - Engelenberg, Charlotte

AU - Soglio, Dorothée Bouron Dal

AU - Priest, John R.

AU - Ragoussis, Jiannis

AU - Foulkes, William D.

PY - 2016

Y1 - 2016

N2 - Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous wholeexome 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, costeffective 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.

AB - Background Somatic mosaicism is being increasingly recognised as an important cause of non-Mendelian presentations of hereditary syndromes. A previous wholeexome 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, costeffective 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.

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