Reclassification of two germline DICER1 splicing variants leads to DICER1 syndrome diagnosis.

Autor: Apellaniz-Ruiz M; Genomics Medicine Unit, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA, Calle Irunlarrea 3, 31008, Pamplona, Navarra, Spain. mv.apellaniz.ruiz@navarra.es., Sabbaghian N; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal, QC, Canada., Chong AL; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal, QC, Canada., de Kock L; Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada., Cetinkaya S; Department of Pediatric Endocrinology, Health Science University, Dr Sami Ulus Obstetrics and Gynecology, Children's Health and Disease Training and Research Hospital, Ankara, Turkey., Bayramoğlu E; Department of Pediatric Endocrinology, Health Science University, Dr Sami Ulus Obstetrics and Gynecology, Children's Health and Disease Training and Research Hospital, Ankara, Turkey., Dinjens WNM; Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands., McCluggage WG; Department of Pathology, Belfast Health and Social Care Trust, Belfast, UK., Wagner A; Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands., Yilmaz AA; Department of Pediatric Endocrinology, Health Science University, Dr Sami Ulus Obstetrics and Gynecology, Children's Health and Disease Training and Research Hospital, Ankara, Turkey., Foulkes WD; Lady Davis Institute, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal, QC, Canada.; Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, QC, Canada.; Department of Medical Genetics, Research Institute of the McGill University Health Centre, Montréal, QC, Canada.
Jazyk: angličtina
Zdroj: Familial cancer [Fam Cancer] 2023 Oct; Vol. 22 (4), pp. 487-493. Date of Electronic Publication: 2023 May 30.
DOI: 10.1007/s10689-023-00336-1
Abstrakt: DICER1 syndrome is an inherited condition associated with an increased risk of developing hamartomatous and neoplastic lesions in diverse organs, mainly at early ages. Germline pathogenic variants in DICER1 cause this condition. Detecting a variant of uncertain significance in DICER1 or finding uncommon phenotypes complicate the diagnosis and can negatively impact patient care. We present two unrelated patients suspected to have DICER1 syndrome. Both females (aged 13 and 15 years) presented with multinodular goiter (thyroid follicular nodular disease) and ovarian tumours. One was diagnosed with an ovarian Sertoli-Leydig cell tumour (SLCT) and the other, with an ovarian juvenile granulosa cell tumour, later reclassified as a retiform variant of SLCT. Genetic screening showed no germline pathogenic variants in DICER1. However, two potentially splicing variants were found, DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somatic DICER1 RNase IIIb hotspot mutations were detected in the thyroid and ovarian tissues. In silico splicing algorithms predicted altered splicing for both germline variants and skipping of exon 25 was confirmed by RNA assays for both variants. The reclassification of the ovarian tumour, leading to recognition of the association with DICER1 syndrome and the characterization of the germline intronic variants were all applied to recently described DICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.
(© 2023. The Author(s).)
Databáze: MEDLINE
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