Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome

Samuela Landini, Benedetta Mazzinghi, Francesca Becherucci, Marco Allinovi, Aldesia Provenzano, Viviana Palazzo, Fiammetta Ravaglia, Rosangela Artuso, Emanuele Bosi, Stefano Stagi, Giulia Sansavini, Francesco Guzzi, Luigi Cirillo, Augusto Vaglio, Luisa Murer, Licia Peruzzi, Andrea Pasini, Marco Materassi, Rosa Maria Roperto, Hans-Joachim AndersMario Rotondi, Sabrina Rita Giglio, Paola Romagnani

Research output: Contribution to journalArticlepeer-review


BACKGROUND AND OBJECTIVES: Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and in silico filtering of 298 genes related to CKD were combined with subsequent reverse phenotyping in patients and families. Pathogenic variants were defined according to current guidelines of the American College of Medical Genetics.

RESULTS: A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.

CONCLUSIONS: Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.

Original languageEnglish
Pages (from-to)89-100
Number of pages12
JournalClinical journal of the American Society of Nephrology : CJASN
Issue number1
Publication statusPublished - Jan 7 2020


Dive into the research topics of 'Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome'. Together they form a unique fingerprint.

Cite this