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04.06.2018 | Original Article

Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93

verfasst von: Martin Bezdíčka, Šárka Štolbová, Tomáš Seeman, Ondřej Cinek, Michal Malina, Naděžda Šimánková, Štěpánka Průhová, Jakub Zieg

Erschienen in: Pediatric Nephrology | Ausgabe 8/2018

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Abstract

Background

Steroid-resistant nephrotic syndrome (SRNS) has a heterogeneous spectrum of monogenic causes that substantially differ among populations. The aim of this study was to analyse the genetic aetiology of SRNS in Czech and Slovak paediatric patients.

Methods

We analysed clinical data from 74 patients (38 boys) with congenital (15%), infant (14%), and childhood-onset (71%) SRNS collected from the Czech Republic and Slovakia from 2000 to 2017 (inclusive). The DNA samples were first analysed by Sanger sequencing (genes NPHS2, NPHS1, and WT1) and then by next generation sequencing (NGS) using a targeted panel of 48 genes previously associated with SRNS. Family segregation of the causative variants was confirmed by Sanger sequencing when possible.

Results

Genetic diagnosis was established in 28/74 patients (38%) based on findings of pathogenic or likely pathogenic causative variants in genotypes conforming to the expected mode of inheritance. Sanger sequencing diagnosed 26% of patients, whereas second-tier testing by a targeted NGS panel diagnosed a further 12%. Frequent causative genes were NPHS2 (15%), WT1 (9.5%), and surprisingly NUP93 with four (5.4%) unrelated cases. Additional causative genes included COQ2 (two patients), NPHS1, INF2, DGKE, and LMX1B (one patient each).

Conclusions

Compared with outright use of NGS, our tiered genetic testing strategy was considerably more rapid and marginally less expensive. Apart from a high aetiological fraction of NPHS2 and WT1 genes, our study has identified an unexpectedly high frequency of a limited set of presumably ancestral causative mutations in NUP93. The results may aid in tailoring testing strategies in Central European populations.

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Titel: Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93
verfasst von: Martin Bezdíčka
Šárka Štolbová
Tomáš Seeman
Ondřej Cinek
Michal Malina
Naděžda Šimánková
Štěpánka Průhová
Jakub Zieg
Publikationsdatum: 04.06.2018
Verlag: Springer Berlin Heidelberg
Erschienen in: Pediatric Nephrology / Ausgabe 8/2018
Print ISSN: 0931-041X
Elektronische ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-018-3950-2

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Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93

Abstract

Background

Methods

Results

Conclusions

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Background

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Conclusions

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