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A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant |
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| Authors: | Nathalia L Gomes Leila CP de Paula Juliana M Silva Thatiana E Silva Antônio M Lerário Mirian Y Nishi Rafael L Batista José A D Faria Júnior Daniela Moraes Elaine MF Costa Tatiana P Hemesath Guilherme Guaragna-Filho Júlio CL Leite Clarissa G Carvalho Sorahia Domenice Eduardo C Costa Berenice B Mendonca |
| Institution: | 1. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, Brazil;2. Hospital de Clínicas de Porto Alegre, Programa de Atendimento às Desordens do Desenvolvimento Sexual (PADS), Unidade de Desordens do Desenvolvimento Sexual Brazil, UFRGS, Rio Grande do Sul, Brazil;3. Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan
Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;4. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular/LIM42, Hospital das Clínicas, Disciplina de Endocrinologia e Metabologia, Faculdade de Medicina da Universidade de São Paulo, Brazil Laboratório de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil |
| Abstract: | Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD. |
| Keywords: | atypical genitalia disorder of sex development 46 XX testicular WT1 |