Genotype–phenotype analysis of pediatric patients with WT1 glomerulopathy

Ahn, Yo Han; Park, Eu Jin; Kang, Hee Gyung; Kim, Seong Heon; Cho, Hee Yeon; Smıth, Lee; Lee, Joo Hoon; Park, Young-Seo; Kim, Kyo Sun; Ha, Il Soo; Cheong, Hae Il

doi:10.1007/s00467-016-3395-4

Cited by 28 publications

(21 citation statements)

References 28 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: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

“…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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“…One 46,XY individual underwent gonadectomy at the age of nine years and was found to have gonadoblastoma. Of the nine 46,XX individuals with WT1 mutations, one individual was found to have absence of ovaries, but DSD was not observed in the remaining eight individuals; later ovarian function was not reported [21]*.…”

Section: Whole-exome Sequencing In Genetic Diagnosis Of Dsdmentioning

confidence: 99%

Recent findings on the genetics of disorders of sex development

Kremen

Chan²,

Swartz³

2017

Current Opinion in Urology

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Purpose of review Disorders of sex development (DSD) are a diverse group of conditions affecting gonadal development, sexual differentiation or chromosomal sex. In this review, we will discuss recent literature on the genetic causes of DSD, with a focus on novel genetic sequencing technologies, new phenotypes associated with known DSD genes, and increasing recognition of the role of genetic regulatory elements in DSD. Methods We performed a comprehensive search of PubMed through August 2016 to identify important peer-reviewed publications from 2015–2016 on the topic of DSD genetics. Summary of Recent Findings Whole-exome sequencing was used to successfully identify genetic causes of DSD in 35% of a cohort of 46,XY subjects who had not previously received a genetic diagnosis. A novel mutation in NR5A1 has been identified as a cause of 46,XX testicular and ovotesticular DSD, demonstrating a previously unappreciated role of NR5A1 in preventing testicular differentiation in 46,XX individuals. Genetic regulatory elements of SOX9 have been identified as causes of 46,XX and 46,XY DSD.

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“…WT1 dominant pathogenic variants are associated with a wide range of clinical phenotypes that are clearly associated with the type and location of the causative WT1 variant. More than 90% of the deleterious variants reside in the hot spot region (exons 8 and 9 and their intronic junctions) [ 6 , 32 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

“…Classically, individuals with WT1 dominant pathogenic variants have been subclassified as having Denys–Drash or Frasier syndrome, however these two syndromes may overlap phenotypically to a certain extent. A number of patients present with a milder phenotype that cannot be easily classified as one of these syndromes [ 32 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet–ESPN inherited glomerulopathy working group

et al. 2020

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Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype–phenotype correlations.

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Genotype–phenotype analysis of pediatric patients with WT1 glomerulopathy

Abstract: WT1 mutations manifest as a wide spectrum of renal and extra-renal phenotypes. Genetic diagnosis is essential for overall management and to predict the genotype-specific risk of DSDs and the development of malignancies.

Cited by 28 publications

References 28 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

Recent findings on the genetics of disorders of sex development

Genetic aspects of congenital nephrotic syndrome: a consensus statement from the ERKNet–ESPN inherited glomerulopathy working group

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