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

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 inDICER1. However, two potentially splicing variants were found,DICER1 c.5365-4A>G and c.5527+3A>G. Also, typical somaticDICER1 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 describedDICER1 variant classification rules. This ultimately resulted in confirmation of DICER1 syndrome in the two teenage girls.
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research