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.

• Klíčová slova
• Next generation sequencing, Rapid diagnosis, Sanger sequencing, Steroid-resistant nephrotic syndrome,
• MeSH
• dítě MeSH
• genetická predispozice k nemoci * MeSH
• genetické testování MeSH
• genotyp MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• kojenec MeSH
• komplex proteinů jaderného póru genetika   MeSH
• lidé MeSH
• longitudinální studie MeSH
• membránové proteiny genetika   MeSH
• mladiství MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• nefrotický syndrom genetika   MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• prospektivní studie MeSH
• proteiny WT1 genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH
• Názvy látek
• intracelulární signální peptidy a proteiny MeSH
• komplex proteinů jaderného póru MeSH
• membránové proteiny MeSH
• nephrin MeSH Prohlížeč
• NPHS2 protein MeSH Prohlížeč
• Nup93 protein, human MeSH Prohlížeč
• proteiny WT1 MeSH
• WT1 protein, human MeSH Prohlížeč