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In 2016, we reported a child with bilateral lung cysts and left lung type II pleuropulmonary blastoma (PPB), classic phenotypes of DICER1 syndrome; we identified a DICER1 hotspot mutation c.5425G>A, p.Gly1809Arg in both a lung cyst and PPB, but the variant was absent in other tissues studied. A somatic mutation (c.1966C>T, p.Arg656Ter) was identified in the PPB, and mosaicism was suspected.1 The child has since developed multinodular goitre (MNG) with cystic thyroid nodules. We have now detected p.Gly1809Arg in the thyroid lesions, while various other tissues were negative. The exquisite localisation of the variant confirms mosaicism and strongly suggests it arose in embryonic foregut endoderm between gestational days 16 and 26.
Mosaicism is a phenomenon where two genetically distinct populations of cells arise following postzygotic acquisition in one cell of a de novo mutation.2 DICER1 syndrome is a paediatric multitumour predisposition syndrome caused typically by germline loss-of-function DICER1 variants, but some predisposing mosaic DICER1 mutations have also been described.1 3 4 DICER1 encodes an endoribonuclease that processes hairpin precursors into mature microRNAs that, in turn, post-transcriptionally regulate target messenger RNA expression. Syndromic tumours result from acquisition of a somatic, second variant that typically affects DICER1’s critical RNase IIIb cleavage domain. These variants are referred to as ‘hotspot mutations’ and include NM_177438.3: c.5425G>A, p.Gly1809Arg. Common phenotypes of DICER1 syndrome include PPB, MNG, cystic nephroma and Sertoli-Leydig cell tumour.
Previously, to assess mosaicism 1 in multiple tissues obtained when the patient’s age ranged from 11 months to age 15 years, DNA was analysed using a Fluidigm Access Array and the HaloPlex HS Target Enrichment System, followed by deep sequencing. However, the results were inconclusive because no completely normal lung tissue was available for study, the p.Gly1809Arg variant was not found in DNA derived from saliva, head hair or blood …
Footnotes
Contributors A-SC performed the DICER1 hotspot sequencing, digital droplet PCR analysis and wrote the manuscript. MA-R performed the DICER1 hotspot sequencing. LdK and BRP edited the manuscript and oversaw some of the laboratory work. WRD provided samples and collected clinical information. DB-DS provided expert pathology opinion. JRP reviewed the diagnostic images, collected clinical information and edited the manuscript. WDF designed the study, wrote and edited the manuscript. All authors read and approved the final manuscript.
Funding This work was funded by a Canadian Institutes of Health Research Grant to WDF (FDN-148390).
Competing interests WDF reports grants from Canadian Institutes of Health Research, during the conduct of the study; grants from Astra Zeneca, outside the submitted work.
Provenance and peer review Not commissioned; externally peer reviewed.
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