Genomic medicine for kidney disease

Abstract

Technologies such as next-generation sequencing and chromosomal microarray have advanced the understanding of the molecular pathogenesis of a variety of renal disorders. Genetic findings are increasingly used to inform the clinical management of many nephropathies, enabling targeted disease surveillance, choice of therapy, and family counselling. Genetic analysis has excellent diagnostic utility in paediatric nephrology, as illustrated by sequencing studies of patients with congenital anomalies of the kidney and urinary tract and steroid-resistant nephrotic syndrome. Although additional investigation is needed, pilot studies suggest that genetic testing can also provide similar diagnostic insight among adult patients. Reaching a genetic diagnosis first involves choosing the appropriate testing modality, as guided by the clinical presentation of the patient and the number of potential genes associated with the suspected nephropathy. Genome-wide sequencing increases diagnostic sensitivity relative to targeted panels, but holds the challenges of identifying causal variants in the vast amount of data generated and interpreting secondary findings. In order to realize the promise of genomic medicine for kidney disease, many technical, logistical, and ethical questions that accompany the implementation of genetic testing in nephrology must be addressed. The creation of evidence-based guidelines for the utilization and implementation of genetic testing in nephrology will help to translate genetic knowledge into improved clinical outcomes for patients with kidney disease.

Figure 1. The genomic nephrology workflow: genetic diagnosis and clinical application

The first step in obtaining a genetic diagnosis for a patient with kidney disease is to characterize their disease phenotype by summarizing their clinical history and other relevant data (for example, findings from biochemical, imaging, and histopathological studies). This phenotype is then used to guide the choice of genetic testing modality. Among patients with genetically heterogeneous disease aetiologies, clinically ambiguous phenotypes, or null results obtained using targeted forms of genetic testing such as Sanger sequencing or targeted next-generation sequencing (NGS) panels, increasingly broad sequencing approaches can be applied, including Mendeliome panels, which can detect variants in all known disease-causing genes; whole-exome sequencing (WES), which can detect variants in all coding regions; and whole-genome sequencing (WGS), which can detect variants in all coding and non-coding regions. Clinical sequence interpretation should be performed according to consensus guidelines^,,. This process involves identifying genes that are relevant to the phenotype of the patient, prioritizing variants on the basis of prior reports in disease cases as well as compatibility with the prevalence and genetic pathogenesis of the associated disease, and assessing the concordance between the genetic findings and the clinical phenotype. If deemed diagnostic, these primary findings, together with secondary findings if the patient has opted to receive them, can be returned and used to inform prognosis and guide personalized care, including targeted work-up and surveillance, choice of therapy, referral for clinical trials and family counselling.