The utility and advantages of exome and genome sequencing in pediatric kidney disease diagnosis.

Abstract

Pediatric kidney diseases encompass a diverse group of disorders, ranging from congenital anomalies to glomerulopathies. Unlike adults, where lifestyle factors predominate, approximately 30% of pediatric cases constitute inherited kidney diseases. This high heritability underscores the critical importance of early and accurate genetic testing. While targeted gene panels have historically been the first-line diagnostic tool, they are limited by fixed gene content and an inability to detect complex structural variants. Next-generation sequencing, specifically exome sequencing and genome sequencing, has transformed the diagnostic landscape by enabling an unbiased, simultaneous analysis of all disease-associated genes. These modalities enhance diagnostic yields by identifying structural variants including copy number variants and non-coding variants often missed by conventional panels. Furthermore, they allow for the discovery of novel disease genes through periodic reanalysis. Despite these advancements, a significant diagnostic gap persists due to the limitations of short-read sequencing in complex genomic regions and the difficulty of interpreting variants of uncertain significance. To address these challenges, integrating long-read sequencing to resolve complex genomic regions and implementing systematic reanalysis protocols are recommended. This review provides a comprehensive comparison of diagnostic yields across testing modalities and discusses the future of genomic profiling in pediatric kidney diseases.