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Review
. 2020 Nov 12;17(22):8363.
doi: 10.3390/ijerph17228363.

Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

Francesca Becherucci  1 , Samuela Landini  2 , Luigi Cirillo  1   2 , Benedetta Mazzinghi  1 , Paola Romagnani  1   2
Affiliations
Review

Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

Francesca Becherucci et al. Int J Environ Res Public Health. .

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a clinical picture defined by the lack of response to standard steroid treatment, frequently progressing toward end-stage kidney disease. The genetic basis of SRNS has been thoroughly explored since the end of the 1990s and especially with the advent of next-generation sequencing. Genetic forms represent about 30% of cases of SRNS. However, recent evidence supports the hypothesis that "phenocopies" could account for a non-negligible fraction of SRNS patients who are currently classified as non-genetic, paving the way for a more comprehensive understanding of the genetic background of the disease. The identification of phenocopies is mandatory in order to provide patients with appropriate clinical management and to inform therapy. Extended genetic testing including phenocopy genes, coupled with reverse phenotyping, is recommended for all young patients with SRNS to avoid unnecessary and potentially harmful diagnostic procedures and treatment, and for the reclassification of the disease. The aim of this work is to review the main steps of the evolution of genetic testing in SRNS, demonstrating how a paradigm shifting from "forward" to "reverse" genetics could significantly improve the identification of the molecular mechanisms of the disease, as well as the overall clinical management of affected patients.

Keywords: genetics; phenocopies; steroid-resistant nephrotic syndrome; whole-exome sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Evolution of genetic diagnosis in steroid-resistant nephrotic syndrome (SRNS). This picture illustrates the advances in the genetic diagnosis of SRNS encompassing technological improvement and analytic strategies. The main cornerstones of sequencing technology development, the genes reported as causative of SRNS and the diagnostic rates are reported. NGS, next-generation sequencing; CKD, chronic kidney disease.
Figure 2
Figure 2
Mechanisms of disease convergence and generation of phenocopies. This picture illustrates the mechanisms responsible for the onset of overlapping clinical phenotypes, namely phenocopies. Monogenic, polygenic, epigenetic and environmental alterations can result in similar phenotypic traits, probably converging on the same functional pathway.
Figure 3
Figure 3
From phenotype to genotype, and back. (A) Genetic testing can be used to confirm the clinical suspect of a genetic disease, looking for mutations in disease-causing genes (from phenotype to genotype). Genetic testing can be performed either with traditional Sanger sequencing (if only one gene can cause the phenotype or if the clinical suspect is extremely high) or with NGS (if more than one gene is known to cause the disease). (B) Extended genotyping can result in unexpected genetic findings (i.e., mutations in genes not classically reported in association with the clinical phenotype of the patient). Reverse phenotyping represents a strategy to verify the hypothesis of a specific genetic diagnosis (from genotype to phenotype). By looking for subtle, previously overlooked clinical signs or symptoms related to the genetic diagnosis, reverse phenotyping can reclassify the diagnosis and initiate personalized clinical management.
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