Diagnostic yield and benefits of whole-exome sequencing in CAKUT patients diagnosed in the first thousand days of life

IntroductionCongenital anomalies of the kidney and urinary tract (CAKUT) are predominant cause chronic disease (CKD) need for replacement therapy (KRT) in children. Although more than 60 genes known to CAKUT if mutated, a genetic etiology is detected on average only 16% unselected cases, making testing unproductive.MethodsWhole-exome sequencing (WES) was performed 100 patients diagnosed first 1,000 days life with CKD stages 1-5D/T. Variants 58 established CAKUT-associated were extracted, classified according ACMG guidelines, their translational value assessed.ResultsIn 25% these mostly sporadic patients, rare likely pathogenic or variant identified one two 15 genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, TBC1D1. Of 27 variants detected, 52% loss-of-function 18.5% de novo variants. The diagnostic yield significantly higher requiring KRT before three years age (43%, odds ratio 2.95) extrarenal features (41%, 3.5) compared lacking criteria. As all affected previously associated complications, treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, hypoparathyroidism, diagnosis allowed preventive measures and/or early treatment patients.ConclusionWES offers significant advantages management age, especially who require have anomalies.