Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants

Nagano, China; Takaoka, Yutaka; Kamei, Koichi; Hamada, Riku; Ichikawa, Daisuke; Tanaka, Kazuki; Aoto, Yuya; Ishiko, Shinya; Rossanti, Rini; Sakakibara, Noburu; Okada, Eri; Horinouchi, Tomoko; Yamamura, Takehira; Tsuji, Yusuke; Noguchi, Yuko; Ishimori, Shingo; Nagase, Hiroaki; Ninchoji, Takeshi; Iijima, Kazumoto; Nozu, Kandai

doi:10.1016/j.ekir.2021.05.009

Cited by 10 publications

(9 citation statements)

References 25 publications

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Section: Discussionsupporting

confidence: 49%

“…However, variants involving other sites in WT1 result in a mild phenotype (including FSGS) (28). Indeed, in this study, all WT1 variants were outside the DNA-binding site and led to slower progression compared with previous findings in patients with Denys-Drash syndrome (29). In previous studies, univariate analyses indicated that the renal prognosis was good in patients with the tip variant of FSGS (10,(20)(21)(22) and poor in patients with the collapsing variant (10,20,21,30).…”

Section: Discussionsupporting

confidence: 40%

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Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis

et al. 2022

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Background: Approximately 30% of children with steroid-resistant nephrotic syndrome (SRNS) have causative monogenic variants. SRNS represents glomerular disease resulting from various etiologies, which lead to similar patterns of glomerular damage. Patients with SRNS mainly exhibit focal segmental glomerulosclerosis (FSGS). There is limited information regarding associations between histological variants of FSGS (diagnosed using on the Columbia classification) and monogenic variant detection rates or clinical characteristics. Here, we report FSGS characteristics in a large population of affected patients. Methods: This retrospective study included 119 patients with FSGS, diagnosed using the Columbia classification; all had been referred to our hospital for genetic testing from 2016 to 2021. We conducted comprehensive gene screening of all patients using a targeted next-generation sequencing panel that included 62 podocyte-related genes. Data regarding patients' clinical characteristics and pathological findings were obtained from referring clinicians. We analyzed the associations of histological variants with clinical characteristics, kidney survival, and gene variant detection rates. Results: The distribution of histological variants according to the Columbia classification was 45% (n=53) FSGS not otherwise specified, 21% (n=25) cellular, 15% (n=18) perihilar, 13% (n=16) collapsing, and 6% (n=7) tip. The median age at end-stage kidney disease onset was 37 years; there were no differences in onset age among variants. We detected monogenic disease-causing variants involving 12 of the screened podocyte-related genes in 34% (40 of 119) of patients. The most common genes were WT1 (23%), INF2 (20%), TRPC6 (20%), andACTN4 (10%). The perihilar and tip variants had the strongest and weakest associations with detection of monogenic variants (83% and 0%, respectively; p<0.001). Conclusions: We revealed the distributions of histological variants of genetic FSGS and non-genetic FSGS in a large patient population. Detailed data concerning gene variants and pathological findings are important for understanding the etiology of FSGS.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionsupporting

confidence: 40%

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis

et al. 2022

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“…According the study reported by Eujin Park ( 15 ) in 2020, WT1 was the most commonly mutated gene in CNS, followed by NPHS1, COQ3 and LAMB2. While in the study by Nagano C from Japan ( 23 ), NPHS1, LAMB2 and WT1 was the most commonly gene detected in CNS. So, the genetic detection rate and the leading genes in CNS vary among different countries and district worldwide.…”

Section: Discussionmentioning

confidence: 91%

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Zhu

Zhang

et al. 2022

Front. Med.

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Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

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“…In this case series and literature review, we were unable to refine the clinical phenotypes with the specific WT1 mutation analyses which have become more available in the recent years. These studies have been able to categorize the various mutations with broader clinicopathologic correlations (39). Over 30 mutations or missense variants of the WT1 protein have been analyzed, reported, and correlated with phenotypes that include proteinuria, ESKD, genital anomalies, and Wilm's tumor (13).…”

Section: Discussionmentioning

confidence: 99%

Spectrum of Clinical Manifestations in Children With WT1 Mutation: Case Series and Literature Review

et al. 2022

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BackgroundMutations of the Wilms tumor suppressor-1 gene (WT1) are associated with life-threatening glomerulopathy, disorders of sexual development, Wilm's tumor, and gonadal malignancies. Our objectives were to describe the clinical presentations, age of progression, and onset of complications of WT1 mutation through a case series and literature review.MethodsA retrospective study included all patients followed at the University of Miami/Holtz Children's Hospital from January 2000 to December 2020 with a diagnosis of WT1 mutation. A literature review of WT1 mutation cases was analyzed for clinical manifestations, karyotype, and long-term outcomes.ResultsThe WT1 mutation was identified in 9 children, median age at presentation of 0.9 years (range 1 week to 7 years). A total of four had female phenotypes, and 5 had abnormalities of male external genitalia, while all had XY karyotypes. All progressed to end-stage kidney disease (ESKD) and received a kidney transplant at a median age of 5 years (1.5–15 years). During a median time of follow-up of 9 years (range 2–28 years), there were 2 allograft losses after 7 and 10 years and no evidence of post-transplant malignancy. From 333 cases identified from the literature review, the majority had female phenotype 66% (219/333), but the predominant karyotype was XY (55%, 183/333). Of the female phenotypes, 32% (69/219) had XY sex reversal. Wilm's tumor occurred in 24%, predominantly in males with gonadal anomalies.ConclusionsEarly recognition of WT1 mutation is essential for comprehensive surveillance of potential malignancy, avoidance of immunosuppressants for glomerulopathy, and establishing long-term multidisciplinary management.

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Genotype-Phenotype Correlation in WT1 Exon 8 to 9 Missense Variants

Cited by 10 publications

References 25 publications

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis

Clinical, Pathological, and Genetic Characteristics in Patients with Focal Segmental Glomerulosclerosis

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study

Spectrum of Clinical Manifestations in Children With WT1 Mutation: Case Series and Literature Review

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