The most common founder pathogenic variant c.868G > A (p.Val290Met) in the NPHS2 gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F23%3A00084475" target="_blank" >RIV/00023001:_____/23:00084475 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11130/23:10472988 RIV/00216208:11110/23:10472988 RIV/00216208:11120/23:43926500 RIV/00216208:11140/23:10472988 and 8 more

Result on the web

<a href="https://www.frontiersin.org/articles/10.3389/fmed.2023.1320054/full" target="_blank" >https://www.frontiersin.org/articles/10.3389/fmed.2023.1320054/full</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3389/fmed.2023.1320054" target="_blank" >10.3389/fmed.2023.1320054</a>

Result language

angličtina

Original language name

The most common founder pathogenic variant c.868G > A (p.Val290Met) in the NPHS2 gene in a representative adult Czech cohort with focal segmental glomerulosclerosis is associated with a milder disease and its underdiagnosis in childhood

Original language description

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&apos; 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 &gt; 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 V290Mrelated 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.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30217 - Urology and nephrology

Project

<a href="/en/project/NV19-06-00443" target="_blank" >NV19-06-00443: Genetics of adult-onset familial focal segmental glomerulosclerosis (FSGS) – implications for individualized therapy and successful kidney transplantation</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2023

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Frontiers in medicine [online]

ISSN

2296-858X

e-ISSN

2296-858X

Volume of the periodical

10

Issue of the periodical within the volume

December 19

Country of publishing house

CH - SWITZERLAND

Number of pages

11

Pages from-to

"art. no. 1320054"

UT code for WoS article

001134851700001

EID of the result in the Scopus database

2-s2.0-85181506495