Human mutation · 2026
Expanding the Molecular Data of DICER1-Related Tumor Predisposition: Novel Germline Variants in an Argentine Pediatric Cohort.
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Trobo Sofía, Garrido Natalia Pérez, Ramírez Pablo, Tesan Fiorella, Vaiani Elisa, Dujovne Noelia, Gazek Natalia, Martí Jessica Lopez, Lavia Mariana, Felizzia Guido, Pringles Victoria, Agotegaray Melisa, Saraco Nora, Ciaccio Marta, Belgorosky Alicia, Marino Roxana
Аннотация
BACKGROUND/OBJECTIVE: DICER1-related tumor predisposition is a rare hereditary tumor predisposition disorder characterized by autosomal dominant inheritance, reduced penetrance, and variable expressivity. This study is aimed at describing the clinical and molecular spectrum of DICER1-related tumor predisposition in an Argentine pediatric cohort.
DESIGN AND METHODS: Seventeen unrelated patients with DICER1-related tumor predisposition and 54 relatives were evaluated at "Prof. Dr. J. P. Garrahan" Pediatric Hospital (Buenos Aires, Argentina) between 2014 and 2024. Germline and somatic DICER1 variants were analyzed using Sanger or next-generation sequencing. Functional assays were performed for selected intronic variants. Three samples of poorly differentiated thyroid carcinoma were also included.
RESULTS: Sixteen distinct germline variants were identified in the 17 index cases, including 12 novel alterations (75%). One quarter of the variants were de novo. Thyroid involvement, particularly multinodular goiter and papillary thyroid carcinoma, was the most common presentation and frequently coexisted with ovarian Sertoli-Leydig cell tumors or embryonal rhabdomyosarcoma. Two novel intronic variants were confirmed to affect splicing by RT-PCR. Somatic "hotspot" mutations in exons 24-25 (RNase IIIb domain) were detected in most tumors, consistent with the two-hit model. The identification of asymptomatic carriers enabled early surveillance and preventive interventions.
CONCLUSIONS: This study expands the molecular spectrum of germline DICER1 variants, reinforces the predominance of thyroid involvement, and highlights the value of molecular testing for diagnosis, genetic counseling, and early intervention. Ethical considerations regarding surveillance and management of asymptomatic carriers remain an important area in need of future guidance.
DESIGN AND METHODS: Seventeen unrelated patients with DICER1-related tumor predisposition and 54 relatives were evaluated at "Prof. Dr. J. P. Garrahan" Pediatric Hospital (Buenos Aires, Argentina) between 2014 and 2024. Germline and somatic DICER1 variants were analyzed using Sanger or next-generation sequencing. Functional assays were performed for selected intronic variants. Three samples of poorly differentiated thyroid carcinoma were also included.
RESULTS: Sixteen distinct germline variants were identified in the 17 index cases, including 12 novel alterations (75%). One quarter of the variants were de novo. Thyroid involvement, particularly multinodular goiter and papillary thyroid carcinoma, was the most common presentation and frequently coexisted with ovarian Sertoli-Leydig cell tumors or embryonal rhabdomyosarcoma. Two novel intronic variants were confirmed to affect splicing by RT-PCR. Somatic "hotspot" mutations in exons 24-25 (RNase IIIb domain) were detected in most tumors, consistent with the two-hit model. The identification of asymptomatic carriers enabled early surveillance and preventive interventions.
CONCLUSIONS: This study expands the molecular spectrum of germline DICER1 variants, reinforces the predominance of thyroid involvement, and highlights the value of molecular testing for diagnosis, genetic counseling, and early intervention. Ethical considerations regarding surveillance and management of asymptomatic carriers remain an important area in need of future guidance.