The most common founder pathogenic variant c.868G > A (p.Val290Met) in the gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood.

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 . In this study, we analyzed the spectrum of 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 gene. The histological classification of FSGS followed the Columbia classification.

Results: 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.

Conclusions: 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.