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.

Chromosomal microarray analysis in fetuses with congenital anomalies of the kidney and urinary tract: A prospective cohort study and meta‐analysis

“…One possible reason for the low detection rate of CMA in CAKUT is that many CAKUT cases were caused by a single gene defect. Up to now, more than 200 monogenic syndromes have been described involving renal or urinary anomalies as one of their features . In one recent study performed by Lei et al, pathogenic variants were identified through whole exome sequencing (WES) in four of 30 fetuses with CAKUT, despite normal findings upon karyotyping and CMA, indicating that WES may further improve the diagnostic rates of CAKUT in prenatal cases.…”

“…Exploring the underlying genetic etiology of CAKUT may improve prenatal diagnosis, genetic counseling, and clinical management. Chromosomal microarray analysis (CMA) has been successfully applied to the identification of copy number variations (CNVs) in pediatric nephropathy and has been shown to be an effective first‐line diagnostic tool in patients with CAKUT . Previous studies have demonstrated that CMA can detect pathogenic CNVs in 4% to 10% of postnatal patients with CAKUT, a diagnostic yield comparable with that noted for the established indications of developmental delay .…”

Renal genetics in Australia: Kidney medicine in the genomic age

“…NGS panel tests to target a pre‐determined set of genes and detect single‐nucleotide variants (SNV) and small insertions or deletions (indels). Targeted testing reduces the risk of incidental findings; however, it relies on the correct gene panel being selected, and the panel content being regularly updated in light of new gene discoveries . In 2013, an expert team of nephrologists, clinical geneticists and molecular geneticists developed an exome‐based panel approach to provide a comprehensive national diagnostic service in Australia.…”

“…Patients should be referred for genetic or genomic testing if it is necessary to confirm a suspected genetic diagnosis, or to clarify or exclude other differential diagnoses . A definitive diagnosis may negate the need for prolonged diagnostic investigations and surveillance . In addition, it may provide prognostic information, including informing targeted surveillance of extra‐renal manifestations .…”

“…Next-generation sequencing (NGS) involves simultaneous sequencing of multiple DNA segments, and may also be referred to as massively parallel sequencing. 7 NGS is able to sequence vast quantities of data compared to traditional Sanger Sequencing techniques, although this is associated with higher error rates. 8 Advances in NGS in the last decade has enabled rapid and cost-effective sequencing of large regions of the genome.…”