Gaining insights into the DICER1 syndrome: An early report from the Italian DICER1 registry.

Abstract

1519 Background: DICER1 is a key endoribonuclease in the microRNA pathway that modulates gene expression. Germline loss of function variants in DICER1, first found in pleuropulmonary blastoma, have been subsequently linked to a variety of cancerous (and non) conditions referred to as DICER1 syndrome. In 2018, the Italian Society of Human Genetics launched an initiative aimed at establishing a national registry of DICER1 germline sequence variants. Methods: Centers involved in genetic testing for cancer predisposition were asked to report any identified DICER1 germline variants and related clinical information. Five University and/or research institutes filled-in the electronic survey. Informed consent was obtained from patients or their legal guardians prior to DNA testing by NGS and/or Sanger sequencing. Results: Six DICER1 sequence variants were identified in 11 individuals. Three missense variants are secondary results of NGS panels for cancer predisposition and lack definitive categorization in online databases. Three previously unreported variants are predicted to be protein truncating and, hence, likely pathogenic. Of these, DICER1 c.4844delA p.(Lys1615Argfs*5) and c.4886C > G p.(Ser1629*) result from ad hoc testing offered to probands based on a history of early onset follicular thyroid carcinoma and botryoid-type embryonal rhabdomyosarcoma of the cervix and of pleuropulmonary blastoma 2nd type, respectively. DICER1 c.4643T > A p.(Leu1548*), instead, results from whole exome sequencing in two siblings with malignant melanoma who tested non informative for alterations in the CDKN2A and CDK4 melanoma predisposing genes. Further investigation unearthed thyroid disease in the family and identified two other young carrier individuals, one unaffected and one thyroidectomized due to multinodular goiter. A DICER1 somatic hot spot sequence variant was detected in goiter specimens. Conclusions: Via the newly established national registry we uncovered novel DICER1 germline sequence variants and uncommon genotype-phenotype associations. Our joint effort will help us to refine our knowledge of the rare DICER1 syndrome , to inform research studies, and to improve testing and clinical management strategies.