#2978 Genetic testing outcomes: insights from a decade of experience at a single center

Le résumé fourni par la source

Abstract Background and Aims Continuous advances in molecular genetics have enabled the diagnosis of an increasing number of genetic kidney diseases in recent years. Establishing a Nephrogenetics' Clinic aims to contribute to better renal care, especially in the era of precision medicine. We present our experience over the past 15 years. Method We conducted a retrospective analysis of genetic testing performed in adult patients since 2010. Since 2015, all patients have been studied with targeted panels based on whole exome sequencing, progressively amplified according to the state of the art. MUC1 was analyzed using Snapshot since 2014 and PKD1 with PCR long range (since 2020). Pre and post genetic counselling were performed by nephrologists and geneticists. Variants of uncertain significance (VUS) were evaluated by geneticists for segregation studies and periodically reclassified. Negative results were reviewed regularly and reanalyzed when relevant. Results A total of 369 index patients were studied, 173 (47%) females, mean age 51.5 years. Until mid-2023, genetic panels with ≤ 85 genes were used. Among 220 patients tested, 15.4% (n = 34) were found to have pathogenic (P) or likely pathogenic (LP) variants. The remaining patients either had VUS or a single pathogenic variant in a gene with autosomal recessive inheritance (n = 85), or their results were negative (n = 101). All reported VUS were reinterpreted, with 17 being reclassified: 8 patients had their VUS upgraded to LP, while 9 were downgraded to benign. In 2023, broader genetic panels, including copy number variation (CNV) analysis, were implemented. Since then, 29.6% (n = 24) of the 81 index cases tested with these broader panels revealed LP/P variants. We identified both a deletion and a microduplication that would have been missed without CNV analysis. Additionally, reanalysis of 24 negative samples using broader panels resulted in positive findings in four of them (17%). Phenotypes at presentation were: 38% glomerular disease, 29% uncharacterized chronic kidney disease (CKD), 18% tubulo-interstitial, 11% cystic and 4% others. Positive results (P and LP variants) in 69 index patients, of which we highlight: 30 COL4; 5 MUC; 1 biallelic REN; 4 UMOD; 2 INF2, 3 PAX2, 4 PKD1, 5 HNF1β; 15 high-risk APOL1 genotypes. Additionally, 1 family (4 patients) was studied for the MUC1 variant by PacBio with positive results. Conclusion Of note, COL4 variants were the most frequent genetic cause of monogenic CKD. ADPKD is probably under-represented in our cohort due to selective testing of atypical cases. The use of broader gene panels and the systematic re-evaluation of variant classifications are pivotal in nephropathy genetic testing. These approaches enable accurate initial diagnoses, facilitating effective patient treatment, family screening, and counseling.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.