Results From the WAGR Syndrome Patient Registry: Characterization of WAGR Spectrum and Recommendations for Care Management

Abstract

WAGR syndrome is a rare genetic disorder characterized by Wilms tumor, Aniridia, Genitourinary anomalies, and Range of developmental delays. In addition to the classic features, patients affected by WAGR syndrome can develop obesity and kidney failure, and a wide variety of non-classical manifestations have also been described. This suggests that a broader phenotypic spectrum beyond the classic syndrome exists and here we demonstrate that spectrum using data from the WAGR Syndrome Patient Registry. In the present study, we collected information from 91 individuals enrolled in the registry to explore self-reported health issues in this patient population. A wide variety of common clinical issues not classically associated with the disorder were found, prompting the redefinition from WAGR syndrome to WAGR spectrum disorder to incorporate the phenotypic variations that occur. A comprehensive care management approach is needed to address the wide range of clinical issues and we propose a care model for patients affected by WAGR spectrum disorder. Further research is needed to solidify the breath of the phenotype and confirm the observations in this study to advance individualized patient care in this population.

Transcriptome-wide association analyses identify an association between ARL14EP and polycystic ovary syndrome

“…Of note, three of the genes (PAX6, BDNF and LRG4) that exhibit evidence for chromatin interactions with the ARL14EP region, have been associated with WAGR (Wilms' tumor, aniridia, genitourinary anomalies, and a range of developmental delays) syndrome [41,42]. Given that one of the symptoms of WAGR syndrome in females includes the presence of non-functional ovaries [43], the interconnected role of these genes in reproductive disorders warrants further investigation.…”

Genetic predisposition to cancers in children and adolescents

“…Clinical features and types of genetic/epigenetic alterations observed in these patients are varied [48,58]. About half of the patients with WAGR develop Wilms tumours [26]. Among patients with BWS, 8-10% develop tumours, including Wilms tumours (3-4%), hepatoblastoma (1-2%) and others [12,48,61].…”

“…Mosaicism can be detected by using NGS or, if detected, may not be reported because of its low frequency. To diagnose chromosomal deletion syndromes, such as WAGR (Wilms tumour, aniridia, genitourinary anomalies, range of developmental delays) syndrome, high-resolution chromosome study, fluorescence in-situ hybridization (FISH), multiplex ligation dependent probe amplification (MLPA) or array-based comparative genomic hybridization (aCGH) are recommended [26]. On the contrary, for other disorders such as BWS, DNA methylation and copy number analysis on chromosome 11p15 are performed [12].…”

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes

“…[25][26][27] In contrast, WAGR spectrum (WT, aniridia, genitourinary abnormalities, and a range of developmental delays), which is caused by a pathogenic germline deletion on 11p13 affect-ing WT1 and PAX6, continues to be regarded as a distinct phenotypic spectrum due to the unique molecular etiology involving deletion of contiguous genes. 23,28,29 Standardized genetic sequencing has identified patients with WT and associated germline WT1 heterozygous pathogenic variants without additional or with only subtle phenotypic features. Since older literature is biased toward recognizable phenotypes, unbiased large cohort studies are needed to better predict the risk of nephrotic syndrome and ESRD in these children and to better assess the phenotypic and genotypic continuum of WT1 disorder.…”

“…Clinical disorders previously considered distinct including Denys Drash syndrome (DDS) and Frasier syndrome are no longer thought to be discrete entities because of the extensive overlap in their clinical manifestations and genetic etiologies 25–27 . In contrast, WAGR spectrum (WT, aniridia, genitourinary abnormalities, and a range of developmental delays), which is caused by a pathogenic germline deletion on 11p13 affecting WT1 and PAX6 , continues to be regarded as a distinct phenotypic spectrum due to the unique molecular etiology involving deletion of contiguous genes 23,28,29 . Standardized genetic sequencing has identified patients with WT and associated germline WT1 heterozygous pathogenic variants without additional or with only subtle phenotypic features.…”