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WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease.
Ferrari, Maria T M; Watanabe, Andreia; da Silva, Thatiane E; Gomes, Nathalia L; Batista, Rafael L; Nishi, Mirian Y; de Paula, Leila C P; Costa, Eduardo C; Costa, Elaine M F; Cukier, Priscilla; Onuchic, Luiz F; Mendonca, Berenice B; Domenice, Sorahia.
Affiliation
  • Ferrari MTM; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Watanabe A; Unidade de Nefrologia Pediátrica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • da Silva TE; Disciplina de Nefrologia, LIM-29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Gomes NL; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Batista RL; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Nishi MY; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • de Paula LCP; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Costa EC; Unidade de Desordens do Desenvolvimento Sexual, UFRGS, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Costa EMF; Unidade de Desordens do Desenvolvimento Sexual, UFRGS, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Cukier P; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Onuchic LF; Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Mendonca BB; Unidade de Nefrologia Pediátrica do Instituto da Criança, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
  • Domenice S; Disciplina de Nefrologia, LIM-29 - Laboratório de Nefrologia Celular, Genética e Molecular, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Sex Dev ; 16(1): 46-54, 2022.
Article in En | MEDLINE | ID: mdl-34392242
Wilms' tumor suppressor gene 1 (WT1) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of WT1 have been classically associated with Denys-Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between WT1 disorders has been frequently observed. New WT1 variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic WT1 variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of WT1 between exons 9 and 10. Two pathogenic missense WT1 variants were identified in two 46,XY individuals with Wilms' tumors; both patients were <1 year of age at the time of diagnosis. A novel WT1 variant, c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with WT1 variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Wilms Tumor / WT1 Proteins / Sexual Development / Kidney Neoplasms Type of study: Risk_factors_studies Limits: Female / Humans / Infant / Male Language: En Journal: Sex Dev Journal subject: CIENCIAS DO COMPORTAMENTO Year: 2022 Document type: Article Affiliation country: Brasil Country of publication: Suiza

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Wilms Tumor / WT1 Proteins / Sexual Development / Kidney Neoplasms Type of study: Risk_factors_studies Limits: Female / Humans / Infant / Male Language: En Journal: Sex Dev Journal subject: CIENCIAS DO COMPORTAMENTO Year: 2022 Document type: Article Affiliation country: Brasil Country of publication: Suiza