Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93
Genetic diagnosis of steroid-resistant nephrotic syndrome in a longitudinal collection of Czech and Slovak patients: a high proportion of causative variants in NUP93
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DOI：
10.1007/s00467-018-3950-2
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发表时间：
2018-08-01
影响因子：
3
通讯作者：
Zieg, Jakub
中科院分区：
文献类型：
--
作者：
Bezdicka, Martin;Stolbova, Sarka;Zieg, Jakub
类固醇耐药肾病综合征（SRNS）具有单基因病因的异质性谱，在人群中存在显著差异。本研究的目的是分析捷克和斯洛伐克儿科患者SRNS的遗传病因，我们分析了2000年至2017年（含）从捷克共和国和斯洛伐克收集的74例先天性（15%）、婴儿（14%）和儿童期发病（71%）SRNS患者（38例男孩）的临床数据。首先通过桑格测序（基因NPHS 2、NPHS 1和WT 1）分析DNA样本，然后使用先前与SRNS相关的48个基因的靶向组进行下一代测序（NGS）。在可能的情况下，通过桑格测序证实致病变异的家族分离。基于符合预期遗传模式的基因型中致病或可能致病的致病变异的发现，在28/74例患者（38%）中建立了遗传诊断。桑格测序诊断了26%的患者，而靶向NGS小组的二级检测诊断了另外12%的患者。常见的致病基因是NPHS 2（15%），WT 1（9.5%），令人惊讶的是NUP 93，其中4例（5.4%）不相关。其他致病基因包括辅酶Q2（两名患者），NPHS 1，INF 2，DGKE和LMX 1B（各一名患者）。与直接使用NGS相比，我们的分层基因检测策略更加快速，成本也更低。除了NPHS 2和WT 1基因的高病因分数之外，我们的研究还发现了NUP 93中有限的一组可能是祖先致病突变的意外高频率。这些结果可能有助于在中欧人群中定制测试策略。
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.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.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).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.