Genetic Analysis in Kidney Disease: Advancing Clinical Diagnosis and Research Discovery

Nephrologists are increasingly including genetic diagnosis into clinical practice as sequencing costs come down, availability improves, and the list of kidney disease genes becomes more complete. Multiple studies suggest that around 10% of the adult ESKD population and 30% of pediatric cohorts have an identifiable genetic kidney disease (1⇓–3). One study found that genetic diagnosis provided new clinical insight in nearly 75% of solved cases by identifying, reclassifying, or specifying disease etiology or informing prognostication, treatment, or transplant decisions (1). Many nephrologists have little experience with genetic testing, and thus, they may have uncertainty about whom to test, what test to select, and what to expect from the genetic results. Kidney disease phenotypes can be caused by mutations in any of hundreds of genes. The exons, which are protein-encoding regions of genes that make up only 1% of the whole genome known as the “exome,” are estimated to carry at least 85% of disease-causing variants (4). Next generation sequencing (NGS), also known as massively parallel sequencing, can evaluate all >18,000 genes or a targeted list of genes. NGS can be done on the whole genome, whole exome, or a selection of genes within the exome; these are known as whole-genome sequencing (WGS), whole-exome sequencing (WES), or targeted NGS, respectively (Figure 1A). Because of their efficient multiplexing, these methods provide a clear advantage over Sanger sequencing individual PCR amplicons for all but a small number of indications. Sequencing of individual variants, such as a known familial variant or specific risk allele, or a short list of genes specified by the phenotype does not require NGS, but the list of genes to evaluate does not need to be long before NGS becomes more cost effective. Large deletions or duplications also known as copy number variations are not detected by …