ESPE2024 Poster Category 1 Sex Endocrinology and Gonads 1 (8 abstracts)
Phenotypic spectrum of WT1 gene variants in DSD
María Celeste Mattone 1 , Carmen Turizo 1 , Natalia Pérez Garrido 1 , Silvia Gil 1 , Pablo Cesar Ramírez 1 , Marino Roxana 1 , María Laura Galluzzo Mutti 2 , Alicia Belgorosky 3,1 , Marta Ciaccio 1 , Esperanza Berensztein 1,4,5 , Gabriela Guercio 1,3 & Mariana Costanzo 1
1Servicio de Endocrinología, Hospital de Pediatría Prof. Dr. J.P. Garrahan, Buenos Aires, Argentina. 2Servicio de Patología, Hospital de Pediatría Prof. Dr. J.P. Garrahan, Buenos Aires, Argentina. 3Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina. 4Facultad de Medicina, Universidad de Buenos Aires (UBA), Buenos Aires, Argentina. 5Facultad de Medicina, Universidad Católica Argentina, Buenos Aires, Argentina
Background: Wilms' Tumor Suppressor Gene 1 (WT1) plays an essential role in urogenital and kidney development. Germline variants in WT1 are associated with life-threatening glomerulopathy, disorders of gonadal development in both 46,XY and 46,XX individuals, Wilms tumor, and gonadal malignancies. Phenotypic overlap among 46,XY affected subjects has been frequently observed and there is still scarce information regarding renal involvement in 46,XX.
Objectives: to describe the phenotype, associated malignancies, and related complications in 14 patients with DSD associated to WT1 variants followed in one single institution.
Materials and Methods: Retrospective study included all patients with DSD and confirmed variants in WT1 gene. Molecular study involved Sanger sequencing, whole exome, and massively parallel targeted sequencing using a DSD-associated gene panel. We retrospectively reviewed the clinical presentation, biochemical phenotype, histological evaluation, and molecular studies.
Results: WT1 variants were identified in 3 out of 30 patients with 46,XX ovotesticular/testicular DSD (10%) and 11 out of 52 patients with 46,XY gonadal dysgenesis (21%). Variants affecting the fourth zinc finger (ZF4) were identified in the three 46,XX subjects, two with testicular and one with ovotesticular DSD. The latter presented germ cell malignancy at early age. None of them had renal involvement (mean follow-up 13 years). Intron 9 spice-site mutations (IVS9) that impaired the expression of KTS+ isoforms of WT1 protein were identified in three patients with 46,XY DSD, two with complete gonadal dysgenesis among which one presented bilateral gonadoblastoma. All subjects with IVS9 variants developed early onset nephropathy leading to kidney transplant before teenage years. Variants in exons 6-9 were detected in six individuals with 46,XY partial gonadal dysgenesis (PGD) and also early onset nephropathy. The two remaining patients presented novel variants classified as likely pathogenic according to ACMG, p.(Tyr266Ter) within exon 3 and c.1264+1G>T in intron 7predicted to impair normal splicing. Both patients presented with 46,XY PGD and bilateral Wilms tumor without nephropathy.
Conclusion: WT1 gene variants are a frequently found in patients with disorders of gonadal development. Renal involvement in 46,XX individuals with ZF4 variants is still uncertain, and although was not present during the follow-up of none of the three subjects in our cohort, long-term assessment is necessary. Despite the significant phenotypic overlap observed among the 46,XY affected subjects, IVS9 variants are linked to more severe gonadal dysgenesis. The report of novel variants, along with the phenotypic data and evolution of affected patients, is crucial in our understanding of these disorders.
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