Pyle, Louise C.

Key Points The growing knowledge of single-gene causes of pediatric-onset kidney diseases necessitates a structured application of genetic testing in practice. The clinical application of a combined nephrogenetics approach for management of kidney diseases is not well described in pediatric settings. Real-world application of a kidney genetics workflow highlights clinical value and challenges to be addressed for its successful implementation. Background The expanding knowledge of identifiable genetic contributions to pediatric inherited kidney diseases, and the increasing availability of genetic testing resources necessitates a combined nephrogenetics clinical approach. Although such models are described for adults, the effect of a structured nephrogenetics workflow on children with inherited kidney disease has not been rigorously evaluated. Methods Clinical and genetic data of patients aged younger than 1–21 years over a 10-year period between 2014 and 2024 from a single-center pediatric inherited kidney disease outpatient program were evaluated. Genetic variants were classified as pathogenic/likely pathogenic and variants of uncertain significance (VUS). Patients were grouped into “informative” or “uninformative” groups based on the effect of genetic test results on disease management and outcomes. Results Of the N =356 patients evaluated for a known or suspected inherited kidney disease, N =188 received clinical genetic testing. Of these, N =147 had an “informative” genetic test affecting at least one positive clinical outcome. Patients with an “informative” genetic test mostly harbored a pathogenic/likely pathogenic variant ( N =122). An additional N =25 had a VUS reclassified as a “VUS-of-interest” affecting a positive outcome measure. Genetic test results led to change in clinical diagnosis (reverse phenotyping, 46%), informed specific diagnosis-based treatment (46%), avoided unnecessary immunosuppression (27%) or kidney biopsy (18%), and guided extrarenal evaluation (72%) in patients with an informative test. Patients with a glomerular (odds ratio [OR]=5.23; 95% confidence interval [CI], 1.96 to 13.96) or a tubular functional disease (OR=2.17; 95% CI, 1.31 to 5.59) were more likely and those with a structural kidney disease (OR=0.39; 95% CI, 0.25 to 0.60) were less likely to receive a genetic test when compared with all other disease categories combined. Conclusions This workflow integrated multidisciplinary care for children with inherited kidney disease and describes a model for actionable clinical care plans after genetic testing. Informative genetic tests were associated with positive outcomes, and notable challenges include access to combined nephrology and genetics expertise for informed testing and an effective result return including VUS interpretation.

Abstract Germline mutations in TP53 cause a rare high penetrance cancer syndrome, Li–Fraumeni syndrome (LFS). Here, we identified a rare TP53 tetramerization domain missense mutation, c.1000G>C;p.G334R, in a family with multiple late-onset LFS-spectrum cancers. Twenty additional c.1000G>C probands and one c.1000G>A proband were identified, and available tumors showed biallelic somatic inactivation of TP53. The majority of families were of Ashkenazi Jewish descent, and the TP53 c.1000G>C allele was found on a commonly inherited chromosome 17p13.1 haplotype. Transient transfection of the p.G334R allele conferred a mild defect in colony suppression assays. Lymphoblastoid cell lines from the index family in comparison with TP53 normal lines showed that although classical p53 target gene activation was maintained, a subset of p53 target genes (including PCLO, PLTP, PLXNB3, and LCN15) showed defective transactivation when treated with Nutlin-3a. Structural analysis demonstrated thermal instability of the G334R-mutant tetramer, and the G334R-mutant protein showed increased preponderance of mutant conformation. Clinical case review in comparison with classic LFS cohorts demonstrated similar rates of pediatric adrenocortical tumors and other LFS component cancers, but the latter at significantly later ages of onset. Our data show that TP53 c.1000G>C;p.G334R is found predominantly in Ashkenazi Jewish individuals, causes a mild defect in p53 function, and leads to low penetrance LFS. Significance: TP53 c.1000C>G;p.G334R is a pathogenic, Ashkenazi Jewish–predominant mutation associated with a familial multiple cancer syndrome in which carriers should undergo screening and preventive measures to reduce cancer risk.