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

Abstract

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> 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 <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> 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 <i>WT1</i> 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 <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> 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 <i>WT1</i> variant<i>,</i> 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 <i>WT1</i> 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.

Phenotypic Variation in 46,XX Disorders of Sex Development due to the Fourth Zinc Finger Domain Variant of WT1: A Familial Case Report

“…This is the first reported familial case of a pathogenic variant of WT1 ZF4. In the earlier reported cases, all nine 46,XX cases of the WT1 ZF4 variants were de novo and exhibited testicular or ovotesticular DSD with atypical external genitalia [Gomes et al, 2019;Eozenou et al, 2020;Sirokha et al, 2021;Ferrari et al, 2022]. Consistently, with the above cases, our proband case showed a similar DSD phenotype.…”

“…This family case suggests that the clinical phenotypes of the WT1 ZF4 variant can be broad in spectrum, ranging from mild reproductive organ defects with normal fertility to sex-reversed DSD or normal renal function to chronic kidney disease (CKD) (Table 1). reported cases (n = 9) [Gomes et al, 2019;Ferrari et al, 2022;Eozenou et al, 2020;Sirokha et al, 2021] present study reported case (n = 1) [Eozenou et al, 2020] present The broad clinical spectrum of 46,XX testicular/ovotesticular DSD cases, as WT1 ZF4 variants, is also reported in the missense variant p.R92W of the NR5A1 gene [Bashamboo et al, 2016;Baetens et al, 2017;. NR5A1 plays an essential role in gonadogenesis and male sex determination and is classically known as one of the most common causative genes for 46,XY DSD [Morohashi et al, 1992;Achermann et al, 1999;Ono and Harley, 2013].…”

Follicular development and ovary aging: single-cell studies

“…M154V mutation of KHDRBS1 (KH RNA binding domain containing, signal transduction associated 1) may result in AS of genes involved in DNA replication and repair, which may affect DNA repair of granulosa cells and/or oocytes, ultimately leading to POI [167]. New WT1 variant-related phenotypes, such as primary ovarian insufficiency, have also been reported, which further emphasizes the status of WT1 in the pathogenesis of POI [168]. Another group compared the fertility of Tet1-lacking mice throughout their reproductive years.…”

The Use of Genetics for Reaching a Diagnosis in XY DSD

“…WT1 abnormalities may also be present in non-syndromic patients [Ferrari et al, 2022]. Usually, WT1 renal disease is manifested by a progressive glomerulopathy associated with younger age at onset (infancy or childhood), but a slow progression of the renal disease, and its manifestations in patients not so young may also occur.…”