Mutational analysis in podocin-associated hereditary nephrotic syndrome in Polish patients: founder effect in the Kashubian population

Abstract

Hereditary nephrotic syndrome is caused by mutations in a number of different genes, the most common being NPHS2. The aim of the study was to identify the spectrum of NPHS2 mutations in Polish patients with the disease. A total of 141 children with steroid-resistant nephrotic syndrome (SRNS) were enrolled in the study. Mutational analysis included the entire coding sequence and intron boundaries of the NPHS2 gene. Restriction fragment length polymorphism (RFLP) and TaqMan genotyping assay were applied to detect selected NPHS2 sequence variants in 575 population-matched controls. Twenty patients (14 %) had homozygous or compound heterozygous NPHS2 mutations, the most frequent being c.1032delT found in 11 children and p.R138Q found in four patients. Carriers of the c.1032delT allele were exclusively found in the Pomeranian (Kashubian) region, suggesting a founder effect origin. The 14 % NPHS2 gene mutation detection rate is similar to that observed in other populations. The heterogeneity of mutations detected in the studied group confirms the requirement of genetic testing the entire NPHS2 coding sequence in Polish patients, with the exception of Kashubs, who should be initially screened for the c.1032delT deletion.

Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations

“…The c.1032delT variant has been previously reported as the most frequent pathogenic variant in NPHS2 in Poland (Kashubian region). 23 Both parents of patient 55 are of Polish extraction. In addition to these two patients, a further 30 had variants without a previous disease association in the following genes: ACTN4 (1 patient), COL4A3 (2), COL4A4 (1), COL4A5 (10), INF2 (2), LAMB2 (2), NPHS1 (5), NPHS2 (2), SMARCAL1 (1), TRPC6 (1) and WT1 (3).…”

Prediction of steroid resistance and steroid dependence in nephrotic syndrome children

“…Also, no m.3243A > G (rs199474657) in MT-TL1 , previously linked to kidney failure, FSGS and SRNS [ 50 , 51 ], was found in this study. Next, we analyzed NPHS2 mutations that have been assigned to 30% of steroid resistant forms of NS in children, especially R138Q (rs574315342) and R229Q (rs1057516414), commonly attributed to SRNS in East Europeans [ 2 , 4 , 52 ]. We spotted no R138Q, whereas 6 patients (3 SR, 2 PSS, 1 SD) and 5 controls had heterozygous R229Q.…”

High prevalence of carriers of variant c.1528G>C of HADHA gene causing long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) in the population of adult Kashubians from North Poland

“…In another study, Lipska et al explored the spectrum of NPHS2 gene mutations causing steroid-resistant nephrotic syndrome in Polish patients and reported that the carriers of the c.1032delT allele were exclusively found in the Pomeranian (Kashubian) region, suggesting a founder effect origin [ 42 ]. Studies of Chmara et al in the population of patients with hypercholesterolaemia suggested that the (c.662A>G variant in the LDLR gene is frequent in this population) [ 23 , 38 , 42 , 43 ].…”