Truncating &lt;b&gt;&lt;i&gt;Wilms Tumor Suppressor Gene 1&lt;/i&gt;&lt;/b&gt; Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report

Hoefele, Julia; Kemper, Markus J.; Schoenermarck, Ulf; Mueller, Susanna; Klein, Hanns‐Georg; Lemke, Anja

doi:10.1159/000450709

Cited by 12 publications

(7 citation statements)

References 17 publications

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“…In 46,XX individuals, two deleterious heterozygous WT1 variants located outside the zinc‐finger domains were previously described in two patients with premature ovarian insufficiency (POI) . Another two 46,XX gonadal dysgenesis patients with steroid‐resistant nephropathy harboured variants located in exon 9 of WT1 . There is no description of atypical genitalia in any of these affected female patients.…”

Section: Discussioncontrasting

confidence: 55%

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

et al. 2018

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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.

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Section: Discussioncontrasting

confidence: 55%

“…14 Another two 46,XX gonadal dysgenesis patients with steroid-resistant nephropathy harboured variants located in exon 9 of WT1. 15,16 There is no description of atypical genitalia in any of these affected female patients.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…Pathogenic WT1 variants have been identified in 46,XX girls with steroid-resistant nephropathy, although their ovarian function evolution has rarely been described [Lipska et al, 2014;Lehnhardt et al, 2015]. There are few reports of abnormal ovarian development in 46,XX patients with pathogenic WT1 variants [Ahn et al, 2017;Hoefele et al, 2017]. Hoefele et al [2017] described a 46,XX patient with adult-onset FSGS and infertility in whom a truncating WT1 variant p.Arg458* was identified.…”

Section: Discussionmentioning

confidence: 99%

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Ferrari

Watanabe

Silva

et al. 2021

Sex Dev

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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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“…WT1 deleterious variants were previously only associated with 46,XY DSD in Denys-Drash and Frasier syndromes. In recent years, the involvement of WT1 in XX gonadal development has been demonstrated by the description of two deleterious heterozygous variants in two 46,XX patients with premature ovarian insufficiency (POI) [68] without kidney disease, and also in a patient with POI and adult-onset focal segmental glomerulosclerosis [69]. Recently, a de novo frameshift variant of WT1 was identified in a girl with 46,XX testicular DSD, c.1453_1456del, p.(Arg485Glyfs*14).…”

Section: Nr5a1 (Sf1) and Wt1: Old Genes New Mechanismsmentioning

confidence: 99%

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Gomes

Chetty

Jørgensen

et al. 2020

IJMS

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Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

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Truncating <b><i>Wilms Tumor Suppressor Gene 1</i></b> Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report

Cited by 12 publications

References 17 publications

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

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

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

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