A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant

Author(s):Show less -

Gomes, Nathalia L. ^[1] ; de Paula, Leila C. P. ; Silva, Juliana M. ^[1] ; Silva, Thatiana E. ^[1] ; Lerario, Antonio M. ^{[2, 3]} ; Nishi, Mirian Y. ^{[2, 1]} ; Batista, Rafael L. ^[1] ; Faria Junior, Jose A. D. ^[1] ; Moraes, Daniela ^[1] ; Costa, Elaine M. F. ^[1] ; Hemesath, Tatiana P. ^[4] ; Guaragna-Filho, Guilherme ^[4] ; Leite, Julio C. L. ^[4] ; Carvalho, Clarissa G. ^[4] ; Domenice, Sorahia ^[1] ; Costa, Eduardo C. ^[4] ; Mendonca, Berenice B. ^{[2, 1]}

Affiliation

^[1] Univ Sao Paulo, Hosp Clin, Unidade Endocrinol Desenvolvimento, Fac Med, Disciplina Endocrinol & Metabol, Lab Hormonios & G, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Med, Lab Sequenciamento Larga Escala SELA, Sao Paulo - Brazil

^[3] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA

^[4] Univ Fed Rio Grande do Sul, Hosp Clin Porto Alegre, Programa Atendimento Desordens Desenvolvimento Se, Unidade Desordens Desenvolvimento Sexual Brazil, Porto Alegre, RS - Brazil

• Document type: Journal article
• Source: Clinical Genetics; v. 95, n. 1, p. 172-176, JAN 2019.
• Web of Science Citations: 3

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. (AU)

• FAPESP's process: 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine
• Grantee: Berenice Bilharinho de Mendonça
• Support Opportunities: Research Projects - Thematic Grants