#2684 DIAGNOSTIC YIELD OF A TARGETED GENE PANEL FOR MONOGENIC KIDNEY DISEASES: A EUROPEAN STUDY
Authors: Giovanella Silvia , Poyatos Andújar Antonio M , Avila-Fernandez Almudena , Bustamante-Aragones Ana , Percesepe Antonio , Martorana Davide , Terracciano Alessandra , Massella Laura , Ligabue Giulia , Testa Francesca , Ferri Camilla , Marino Marco , Tagliafico Enrico , Calabrese Olga , Donati Gabriele , Magistroni Riccardo 
Published: June 2023

Background and Aims

Despite advances in understanding the underlying causes of CKD, 20% of cases remain unexplained (1). A genomic approach has the potential to identify the cause of CKD in a significant portion of pediatric and adult patients, with estimated diagnostic rates of 5-30% (2). However, there is a lack of consensus in the scientific community on the best diagnostic algorithm. The DECIDE project (Diagnostic EffiCacy kIdney Disease European) is a European collaboration that aims to address this issue by evaluating the diagnostic rate of a targeted gene panel in a large cohort of patients.

Method

DECIDE involved three Italian and two Spanish centers, encompassing both pediatric and adult patients. The study used the Nephropathies Solution Panel (NES, SOPHiA Genetics), which covers 44 kidney-related genes, to test patients with a high suspicion of genetic kidney disease. The clinical presentation was classified into cystic disease, glomerulopathy, CAKUT, tubulopathy, nephrocalcinosis, other, and negative phenotype. The diagnostic yield of the NES panel was calculated. To assess the genotype-phenotype relationship, Kaplan-Meier analyses were performed. Additionally, the diagnostic results obtained from alternative technologies, such as larger panels, WES and hybridization arrays, in cases of NES panel negative results, were also collected.

Results

As far as now the DECIDE project collected 632 genetic data. To evaluate the diagnostic accuracy of the panel, the number of (likely) pathogenic variants correlated to phenotype was analyzed. The diagnostic yield is shown in Figure 1, with 46% for cystic disease, 41% for glomerulopathy, 33% for tubulopathies, 28% for CAKUT, 14% for nephrocalcinosis, 2% for negative (in the context of segregation analyses or in cascade test) and 8% for other. Table 1 shows that the main genes involved in the diagnosis were PKD1, PKD2, COL4A3, COL4A4, and COL4A5. In patients affected by cystic disease, the mean age of kidney failure was 48 years in the presence of diagnostic variants, 59 years for VUS, and no events were reported in patients with negative tests. The Kaplan-Meier curve confirmed a worse prognosis in patients with diagnostic variants (p-value&lt;0.05). However, no significant genotype-phenotype correlation in terms of time to replacement therapy was observed in glomerulopathic patients. In cases of non-diagnostic results, 21 further investigations were performed. An enriched panel for cystic disease didn't detect any diagnostic variants, while only one patient was diagnosed using WES. The Hybridization Array identified a gene deletion that is under investigation and may be related to the phenotype (Nephronophthisis).

Conclusion

The preliminary results of the DECIDE project, based on about 600 data, demonstrate the potential of the NES panel in the diagnosis of kidney genomic disease. The panel showed a good diagnostic yield for cystic disease (46%) and glomerulopathy (41%), but it appears less effective in other clinical presentations. The average diagnostic yield of the panel was comparable to published data for gene panel and WES approaches. However, additional tests such as larger gene panels, WES, or CGH-array were found to be of limited usefulness, as they only identified one pathogenic variant. These results suggest that new approaches are necessary to uncover the hidden genetic components of rare renal conditions.