Next-generation sequencing-based genetic diagnosis of steroid-resistant nephrotic syndrome: Benefits and challenges

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is the second-most common cause of chronic kidney disease in children and in those requiring kidney transplantation. The disease shows significant heterogeneity in its age at onset and clinical course. The discovery of mutations in NPHS1, the gene encoding nephrin that is a key component of the podocyte slit diaphragm, in a subset of children with congenital NS, led to identification of a distinct subgroup of patients of SRNS that has an underlying genetic etiology. Subsequently, mutations in over 53 podocyte genes have been implicated in monogenic forms of SRNS with no clear genotype-phenotype correlations. The large number of genes implicated in SRNS, phenotypic variability, and lack of information about frequency of mutations in these genes, makes the use of genetic testing in the management of children with SRNS challenging in terms of decisions on who to test, which genes to screen, and how to use the information obtained from testing in the clinical setting. Given the genetic heterogeneity and phenotypic variability, Sanger sequencing is not a feasible approach for routine testing. Next-generation sequencing (NGS) technology is emerging as the preferred method to screen multiple genes in genetically heterogeneous diseases like SRNS. Such high-throughput sequencing method permits rapid and cost-effective simultaneous screening of large number of individuals and genes. However, the high throughput combined with significant phenotypic and genetic variability of monogenic SRNS poses unique challenges for clinicians in the interpretation of genetic result. This review provides an overview of utility of genetic testing with focus on NGS-based genetic testing and the challenges in the interpretation of genetic results in clinical settings.