# Estimation of the Age of the Kashubian-Specific Pathogenic NPHS2 Variant Responsible for Hereditary Steroid-Resistant Nephrotic Syndrome Points to Its Recent Local Origin

## TL;DR

This study identifies a recent origin of a harmful NPHS2 gene variant in the Kashubian population, which causes kidney disease and could inform targeted screening.

## Contribution

The study provides the first estimation of the age of a Kashubian-specific NPHS2 pathogenic variant using haplotype analysis.

## Key findings

- The c.1032delT NPHS2 variant originated approximately 240 years ago in the Kashubian population.
- The variant is associated with a specific haplotype background unique to Kashubians.
- The mutation is responsible for nearly all cases of SRNS in Kashubian families studied.

## Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a highly heterogenic kidney disorder resulting from genetic abnormalities or immune system dysfunction affecting the establishment and maintenance of the glomerular filtration barrier. The most common cause of genetic SRNS is biallelic pathogenic variants in NPHS2 gene, especially in individuals with an infantile or childhood onset. The type of the NPHS2 defect implies the course of the disease and the stage of its onset and differs across populations. In a cohort of Polish patients with SRNS, a unique profile of the disease-related NPHS2 variants was identified in patients from northern Poland inhabited by Kashubs, a minority West-Slavic ethnic group known for a local increase of the frequency of several pathogenic variants. Among Kashubian families, the compound heterozygotes c.686G>A/c.1032delT and a single c.1032delT homozygote were the only underlying cause of SRNS. The restricted, Kashubian-only pattern of c.1032delT occurrence, suggesting the founder effect, prompted us to conduct a detailed analysis of its haplotype background to estimate the age of the c.1032delT origin. Eight Kashubian SRNS families were genotyped using the Infinium Global Screening Array-24. The haplotype background analysis was performed using an in-house pipeline designed to solve the phase of the heterozygous genotype data. The age of the c.1032delT mutation was calculated using the gamma method based on the genetic length of ancestral haplotypes shared between two or more individuals carrying this variant. The results of our study indicated a very recent origin of the c.1032delT mutation (~240 years). Genetic screening performed in the general Polish population control corroborates the assumption that the mutation occurred on the specific Kashubian haplotype background. The identification of ancestry-specific Kashubian pathogenic variant can help to develop effective screening and diagnostic strategies as a part of personalized medicine approach in the region.