Genomic profiling in (recurrent) steroid-resistant nephrotic syndrome

类固醇抵抗性肾病综合征和局灶节段性肾小球硬化（SRNS/FSGS）的临床和遗传异质性谱构成了全球儿童和成人发病终末期肾病（ESRD）的主要原因。尽管在这一领域进行了20多年的遗传学研究，但仍有相当数量的ESRD患者（儿童总发病率为60%）没有得到明确的诊断。特别是成年患者的基因检测服务不足，只有零散的基因型数据存在。肾脏替代疗法（透析和肾移植）是唯一的治疗选择，但需要医疗资源，世界上大多数患者根本无法获得。很大一部分患有FSGS的儿童和成人（约30%）在移植物中出现FSGS复发（FSGS- r）。FSGS-R的病理生理基础尚不清楚。自从KFO 329的公告和SRNS/FSGS基因组分析项目（TP 8）的信息公开以来，我们收到了大量的积极反馈，并在2个月内招募了45名FSGS患者和11名FSGS- r患者。借助新的DFG测序呼叫和CCG的NovaSeq6000平台的可用性，我们希望将我们的项目扩展到100个SRNS/FSGS病例的额外外显子组和90个基因组用于FSGS-(R)的单例或三组分析。因此，我们希望满足KFO最初审稿人的善意批评，即通过增加WGS和WGS/WES Trio分析的数量，基因寻找策略可以更具竞争力，而这些分析在最初的预算限制提案中受到限制，而不会影响研究的完全性。

The clinical and genetically heterogeneous spectrum of steroid resistant nephrotic syndrome and focal segmental glomerulosclerosis (SRNS/FSGS) constitutes a major cause of pediatric as well as adult onset endstage renal disease (ESRD) worldwide. Despite over 20 years of genetic studies in this field a substantial number of patients with ESRD (overall > 60% in children) are still left without a clear diagnosis. Especially adult patients have been underserved with genetic testing and only fragmented data on their genotypes exits. Renal replacement therapy (dialysis and kidney transplantation) is the only treatment option, but requires medical resources that are simply not available to most patients worldwide. A significant proportion of children and adults with FSGS (ca. 30%) experience recurrence of FSGS in the graft (FSGS-R). The pathophysiologic basis of FSGS-R remains still unclear. Since announcement of the KFO 329 and information on the SRNS/FSGS genomic profiling project (TP 8) went public we have received enormous positive feedback and have been able to recruit 45 additional FSGS patients and 11 patients with FSGS-R within a 2 months period. With the help of the new DFG sequencing call and the availability of the NovaSeq6000 platform at the CCG we would like to expand our project to 100 additional exomes of SRNS/FSGS cases and 90 genomes for singleton or trio analyses in FSGS-(R). Thereby, we want to meet the benevolent critique of the initial reviewers of the KFO that the gene hunting strategy could be more competitive by increasing the number of WGS and WGS/WES Trio analyses that have been limited in the original proposal for budget restrictions without compromising the thoroughness of the study.