Clinical Characterization of a National Cohort of Patients With Germline WT1 Variants Including Late-Onset Phenotypes

IF 5.7 2区 医学 Q1 UROLOGY & NEPHROLOGY
Sophie E. van Peer , Roland P. Kuiper , Janna A. Hol , Sanne Egging , Bert van der Zwaag , Marc R. Lilien , M. Paola Lombardi , Marry M. van den Heuvel-Eibrink , Marjolijn C.J. Jongmans
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引用次数: 0

Abstract

Introduction

WT1 disorder is a recently introduced term for phenotypes associated with germline Wilms Tumor 1 (WT1) variants, including glomerulopathy, urogenital anomalies, and Wilms tumor. Previous studies showed a bias toward missense variants in the DNA-binding/Zinc-finger domain of WT1 (exon 8 and 9) and patients with early-onset glomerulopathy. Thorough genotype-phenotype correlations including follow-up data on late-onset glomerulopathy risk are lacking. To characterize the genotypic and phenotypic spectrum of WT1 disorder, we describe a national cohort of individuals with WT1 variants.

Methods

We requested clinical and genetic data of all patients with germline WT1 variants at all Dutch genetic laboratories.

Results

We identified 43 patients with pathogenic WT1 variants (truncating, n = 19; missense, n = 13; splice-site, n = 7; and deletions, n = 4). Wilms tumor was the only clinical manifestation in 10 patients, of whom 9 were female. Wilms tumor occurred in 18 of 19 patients with truncating variants, in 4 of 4 patients with deletions, and was rarer in patients with missense or splice-site variants. All patients with missense and 6 of 7 with splice-site variants developed chronic kidney disease (CKD) versus 5 of 19 patients with truncating variants (3 in adulthood, with kidney failure at the age of 24, 26, and 41 years) and 1 of 4 with a deletion. Urogenital malformations occurred predominantly in 46,XY individuals.

Conclusion

Among patients with WT1 variants, a genotype-phenotype correlation was observed for Wilms tumor risk and age of CKD onset. Although childhood-onset CKD was more common in patients with missense variants in the DNA-binding/Zinc-finger domain, other patients may develop CKD and kidney failure later in life. Therefore, life-long surveillance of kidney function is recommended. Being alert about WT1 variants is especially important for girls with Wilms tumor who often miss additional phenotypes.

Abstract Image

包括迟发性表型在内的种系WT1变异患者的全国队列临床特征
简介:WT1疾病是最近引入的一个术语,用于描述与种系肾母细胞瘤1 (WT1)变异相关的表型,包括肾小球病变、泌尿生殖系统异常和肾母细胞瘤。先前的研究表明,在WT1的dna结合/锌指结构域(外显子8和9)和早发性肾小球病变患者中存在错义变异。缺乏全面的基因型-表型相关性,包括迟发性肾小球病变风险的随访数据。为了描述WT1疾病的基因型和表型谱,我们描述了一个具有WT1变异个体的国家队列。方法:我们要求所有荷兰遗传实验室的所有种系WT1变异体患者的临床和遗传数据。结果:我们鉴定出43例WT1致病性变异患者(截断,n = 19;错义,n = 13;剪接位点,n = 7;和缺失,n = 4)。10例患者中仅有Wilms肿瘤的临床表现,其中9例为女性。19例截断型变异体患者中有18例发生Wilms肿瘤,4例缺失型变异体患者中有4例发生Wilms肿瘤,而错义型或剪接位点变异体患者发生Wilms肿瘤的几率较低。所有错义患者和7例剪接位点变异患者中有6例发展为慢性肾脏疾病(CKD),而19例截断变异患者中有5例(3例在成年期,24岁、26岁和41岁时肾功能衰竭)和4例缺失患者中有1例。泌尿生殖系统畸形主要发生在46,xy个体中。结论:在WT1变异体患者中,Wilms肿瘤风险与CKD发病年龄存在基因型-表型相关性。尽管儿童期CKD在dna结合/锌指结构域错义变异的患者中更为常见,但其他患者可能在以后的生活中发展为CKD和肾衰竭。因此,建议终生监测肾功能。对于患有Wilms肿瘤的女孩来说,警惕WT1变异尤其重要,因为她们经常错过其他表型。
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来源期刊
Kidney International Reports
Kidney International Reports Medicine-Nephrology
CiteScore
7.70
自引率
3.30%
发文量
1578
审稿时长
8 weeks
期刊介绍: Kidney International Reports, an official journal of the International Society of Nephrology, is a peer-reviewed, open access journal devoted to the publication of leading research and developments related to kidney disease. With the primary aim of contributing to improved care of patients with kidney disease, the journal will publish original clinical and select translational articles and educational content related to the pathogenesis, evaluation and management of acute and chronic kidney disease, end stage renal disease (including transplantation), acid-base, fluid and electrolyte disturbances and hypertension. Of particular interest are submissions related to clinical trials, epidemiology, systematic reviews (including meta-analyses) and outcomes research. The journal will also provide a platform for wider dissemination of national and regional guidelines as well as consensus meeting reports.
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