Thomasová Dana, Zelinová Michaela, Libik Malgorzata, Geryk Jan, Votýpka Pavel, Rajnochová Bloudíčková Silvie, Krejčí Karel, Reiterová Jana, Jančová Eva, Machová Jana, Kollárová Martina, Rychík Ivan, Havrda Martin, Horáčková Miroslava, Putzová Martina, Šafránek Roman, Kollár Marek, Macek Milan
Institute of Biology and Medical Genetics, University Hospital Motol and 2nd Faculty of Medicine, Charles University Prague, Prague, Czechia.
Department of Nephrology, Institute for Clinical and Experimental Medicine, Prague, Czechia.
Front Med (Lausanne). 2023 Dec 19;10:1320054. doi: 10.3389/fmed.2023.1320054. eCollection 2023.
Genetic focal segmental glomerulosclerosis (FSGS) is caused by pathogenic variants in a broad spectrum of genes that have a variable representation based on subjects' ethnicity and/or age. The most frequently mutated autosomal recessive gene in FSGS is . In this study, we analyzed the spectrum of variants and their associated phenotype in Czech adult FSGS patients.
A representative cohort of 234 adult patients with FSGS, derived from 225 families originating from all regions of Czechia, was analyzed by massively parallel sequencing. In this study, we focused on the comprehensive analysis of the gene. The histological classification of FSGS followed the Columbia classification.
We detected seven (3%) cases bearing homozygous or compound heterozygous pathogenic variants. A single pathogenic variant c.868G > A (p.Val290Met) was found in the majority of -positive cases (86%; 6 out of 7) in histologically confirmed instances of FSGS. Its allele frequency among unrelated -associated FSGS patients was 50% (6/12), and Haplotype analysis predicted its origin to be a result of a founder effect. There is an identical V290M-related haplotype on all V290M alleles spanning a 0,7 Mb region flanking in Central European FSGS populations. The phenotype of the p.Val290Met -associated FSGS demonstrated a later onset and a much milder course of the disease compared to other pathogenic variants associated with FSGS. The mean age of the FSGS diagnosis based on kidney biopsy evaluation was 31.2 ± 7.46 years. In 50% of all cases, the initial disease manifestation of proteinuria occurred only in adulthood, with 83% of these cases not presenting with edemas. One-third (33%) of the studied subjects progressed to ESRD (2 out of 6) at the mean age of 35.0 ± 2.82 years.
We identified the most prevalent pathogenic variant, p.Val290Met, in the gene among Czech adult FSGS patients, which has arisen due to a founder effect in Central Europe. The documented milder course of the disease associated with this variant leads to the underdiagnosis in childhood. We established the histopathological features of the -associated adult FSGS cases based on the Columbia classification. This might improve patient stratification and optimize their treatment.
遗传性局灶节段性肾小球硬化（FSGS）由多种基因的致病变异引起，这些基因的表现因受试者的种族和/或年龄而异。FSGS中最常发生突变的常染色体隐性基因是 。在本研究中，我们分析了捷克成年FSGS患者中 变异的谱系及其相关表型。
通过大规模平行测序分析了来自捷克共和国所有地区的225个家庭的234名成年FSGS患者的代表性队列。在本研究中，我们专注于对 基因的全面分析。FSGS的组织学分类遵循哥伦比亚分类法。
我们检测到7例（3%）携带纯合或复合杂合致病变异的病例。在组织学确诊的FSGS病例中，大多数 阳性病例（86%；7例中的6例）发现了单一致病变异c.868G>A（p.Val290Met）。在无关的 相关FSGS患者中，其等位基因频率为50%（6/12），单倍型分析预测其起源是奠基者效应的结果。在中欧FSGS人群中，所有V290M等位基因上都有一个相同的与V290M相关的单倍型，跨越 侧翼0.7 Mb区域。与其他与FSGS相关的致病变异相比，p.Val290Met相关的FSGS表型表现为发病较晚且病程较轻。基于肾活检评估的FSGS诊断平均年龄为31.2±7.46岁。在所有病例的50%中，蛋白尿的初始疾病表现仅发生在成年期，其中83%的病例没有水肿。三分之一（33%）的研究对象在平均年龄35.0±2.82岁时进展为终末期肾病（6例中的2例）。
我们在捷克成年FSGS患者中鉴定出 基因中最常见的致病变异p.Val290Met，其起源于中欧的奠基者效应。与该变异相关的疾病病程较轻，导致儿童期诊断不足。我们根据哥伦比亚分类法确定了 相关成年FSGS病例的组织病理学特征。这可能会改善患者分层并优化他们的治疗。
