BACKGROUND: 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 NPHS2. In this study, we analyzed the spectrum of NPHS2 variants and their associated phenotype in Czech adult FSGS patients. METHODS: 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 NPHS2 gene. The histological classification of FSGS followed the Columbia classification. RESULTS: We detected seven (3%) cases bearing homozygous or compound heterozygous pathogenic NPHS2 variants. A single pathogenic variant c.868G > A (p.Val290Met) was found in the majority of NPHS2-positive cases (86%; 6 out of 7) in histologically confirmed instances of FSGS. Its allele frequency among unrelated NPHS2-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 NPHS2 in Central European FSGS populations. The phenotype of the p.Val290Met NPHS2-associated FSGS demonstrated a later onset and a much milder course of the disease compared to other NPHS2 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. CONCLUSIONS: We identified the most prevalent pathogenic variant, p.Val290Met, in the NPHS2 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 NPHS2-associated adult FSGS cases based on the Columbia classification. This might improve patient stratification and optimize their treatment.

3rd Department of Internal Medicine Nephrology Rheumatology and Endocrinology University Hospital and Faculty of Medicine Palacký University Olomouc Olomouc Czechia

Biomedical Centre Faculty of Medicine in Pilsen Charles University Pilsen Czechia

Biopticka Laboratory Pilsen Czechia

Department of Internal Medicine 1 Faculty of Medicine in Pilsen Charles University and Teaching Hospital Pilsen Czechia

Department of Internal Medicine University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Czechia

Department of Internal Medicine University Hospital Vinohrady and 3rd Faculty of Medicine Charles University Prague Czechia

Department of Nephrology General University Hospital Prague 1st Faculty of Medicine Charles University Prague Czechia

Department of Nephrology Institute for Clinical and Experimental Medicine Prague Czechia

Department of Nephrology University Hospital Hradec Králové Faculty of Medicine in Hradec Králové Charles University Hradec Králové Czechia

Department of Pathology Institute for Clinical and Experimental Medicine Prague Czechia

Faculty of Medicine in Plzeň Charles University Pilsen Czechia

Institute of Biology and Medical Genetics University Hospital Motol and 2nd Faculty of Medicine Charles University Prague Prague Czechia

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