Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

Keywords: Focal segmental glomerulosclerosis; Genetic testing; Monogenic; Mutational screening; Steroid-resistant nephrotic syndrome.

Fig. 1

Genetic mutations associated with steroid-resistant nephrotic syndrome (SRNS) grouped according to location and function within the glomerular filtration barrier. For full names of proteins encoded by genes, please refer to Table 1

Fig. 2

Mutational screening in children with isolated SRNS. If next-generation sequencing (NGS) technology is accessible, screening should utilise a gene panel including, but not limited to, the most common monogenic causes of SRNS. If NGS technology is inaccessible, genes should be screened in numerical order of frequency per age group. Ethnicity and histological findings should trigger preferential screening of certain genes. DMS Diffuse mesangial sclerosis. For names of genes and associated encoded proteins, please refer to Table 1