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

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...

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Bibliographic Details
Published in:	Clinical genetics Vol. 95; no. 1; pp. 172 - 176
Main Authors:	Gomes, Nathalia L., de Paula, Leila C.P., Silva, Juliana M., Silva, Thatiana E., Lerário, Antônio M., Nishi, Mirian Y., Batista, Rafael L., Faria Júnior, José A. D., Moraes, Daniela, Costa, Elaine M.F., Hemesath, Tatiana P., Guaragna‐Filho, Guilherme, Leite, Júlio C.L., Carvalho, Clarissa G., Domenice, Sorahia, Costa, Eduardo C., Mendonca, Berenice B.
Format:	Journal Article
Language:	English
Published:	Oxford, UK Blackwell Publishing Ltd 01-01-2019
Subjects:	46, XX Disorders of Sex Development - diagnosis 46, XX Disorders of Sex Development - genetics 46, XX Disorders of Sex Development - pathology atypical genitalia Child disorder of sex development; 46,XX testicular DNA-Binding Proteins - genetics Female Genitalia Gonadal dysgenesis Heterozygote Humans Infant Male Mutation Pathology, Molecular Phenotype Phenotypes Sex Sexual Development - genetics Testes Testicular Diseases - diagnosis Testicular Diseases - genetics Testicular Diseases - pathology Testis - pathology Tumors WT1 WT1 Proteins - genetics Zinc finger proteins disorder of sex development; 46,XX testicular WT1 atypical genitalia
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-9163 1399-0004
DOI:	10.1111/cge.13459