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Abstract: SA-PO396

Reverse Phenotyping After Whole-Exome Sequencing Reveals Frequent Podocytopathy Phenocopies in Steroid-Resistant Nephrotic Syndrome

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Becherucci, Francesca, University of Florence, Florence, Italy
  • Landini, Samuela, University of Florence, Florence, Italy
  • Mazzinghi, Benedetta, A.O.U Meyer, Firenze, Italy
  • Allinovi, Marco, Careggi University Hospital, Firenze, Italy
  • Guzzi, Francesco, University of Florence, Florence, Italy
  • Cirillo, Luigi, University of Florence, Florence, Italy
  • Anders, Hans J., Klinikum der Universitat Munchen, Muenchen, Germany
  • Giglio, Sabrina, University of Florence, Florence, Italy
  • Romagnani, Paola, University of Florence, Florence, Italy
Background

Primary idiopathic nephrotic syndrome (NS) is a typical presentation of genetic or non-genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that such phenocopies of steroid resistant NS (SRNS) represent a relevant percentage of patients with primary NS explaining frequent multi-drug resistance.

Methods

All patients affected by primary NS referred to our center between 2000 and 2018 were included in the study. Whole-exome sequencing and in silico filtering of 298 nephropathic genes were combined with reverse phenotyping performed right after genetic diagnosis in all the patients and families.

Results

A total of 111 patients (64 SRNS and 47 steroid sensitive NS, SSNS) were included in the final analysis. Not a single pathogenic variant was detected in the SSNS group. As expected, 20/64 (31.3%) SRNS patients had pathogenic variants in podocyte genes. However, 17/64 (26.6%) showed pathogenic variants in many other genes related to clinically unrecognized genetic nephropathies, i.e. in the absence of clinical signs of the underlying disorder at onset. Reverse phenotyping permitted the identification of minor clinical signs of the underlying genetic nephropathy in the patient or the family, confirming the diagnosis and explaining multi-drug resistance. Genetic patients did not experience recurrence of post-transplant NS (0/11), while NS relapsed in 40% of the others (4/10).

Conclusion

Our unique interdisciplinary workflow based on extended genetic analysis and reverse phenotyping can significantly increase the diagnostic accuracy in patients referred with the diagnosis of SRNS, avoiding mistreatment and predicting outcome in a large percentage of these patients.