Article Text

Short report
A complex DICER1 syndrome phenotype associated with a germline pathogenic variant affecting the RNase IIIa domain of DICER1
  1. Emeli Pontén1,
  2. Sofia Frisk1,2,
  3. Fulya Taylan1,2,
  4. Raquel Vaz1,
  5. Sandra Wessman3,
  6. Leanne de Kock4,
  7. Niklas Pal5,
  8. William D Foulkes4,
  9. Kristina Lagerstedt-Robinson1,2,
  10. Ann Nordgren1,2
  1. 1Department of Molecular Medicine and Surgery (MMK), Karolinska Institute, Stockholm, Sweden
  2. 2Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  3. 3Oncology-Pathology, Karolinska University Hospital, Stockholm, Sweden
  4. 4Departments of Human Genetics, Oncology, Medicine, McGill University, Montreal, Québec, Canada
  5. 5Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden
  1. Correspondence to Professor Ann Nordgren, Dept of Molecular Medicine and Surgery (MMK), Karolinska Institute, 171 64 Stockholm, Sweden; ann.nordgren{at}


Background Germline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW (Global developmental delay, Lung cysts, Overgrowth, Wilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain.

Methods Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed.

Results A de novo heterozygous c.4031C>T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome.

Conclusion The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an individual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.

  • genetic predisposition to disease
  • genetics
  • medical
  • genomics

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  • KL-R and AN are joint senior authors.

  • Contributors AN coordinated the study. AN and KLR performed WGS analyses. NP provided clinical care. SW, SF, WDF, AN and NP performed clinical and pathological phenotyping. SF and FT performed digital PCR. EP, SF, FT, AN, RV, NP, WDF, LdK and KLR contributed with data collection, interpretation and discussion of results. EP and AN wrote the manuscript in consultation with all authors.

  • Funding This work was supported by grants from the Swedish Childhood Cancer Fund, the Swedish Cancer Society, the Cancer Society of Stockholm, the Swedish Research Council, Berth von Kantzow’s Foundation and The Hållsten Research Foundation.

  • Competing interests WDF reports support from AstraZeneca, outside the submitted work (VUS classification project in breast cancer gene sequencing project).

  • Patient consent for publication Parental/guardian consent obtained.

  • Ethics approval The local Ethics Committee at Karolinska Institute approved the study (Dnr 2012-2106-31/4), which followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from the parents.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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