Abstract

Background and aims Steroid-resistant nephrotic syndrome (SRNS) is the rare disease and holds a special place in structure of nephrotic syndrome in children, it takes up to 15–25% among other forms of the nephrotic syndrome. SRNS is one of the most common causes of end-stage kidney failure. The majority of SRNS cases are caused by genetic mutations leading to structural and functional glomerular injuries. Treatment strategy in children with SRNS is defined by results of molecular genetic testing and morphological diagnosis after kidney biopsy. Research is focused on identification of pathogenic gene variants leading to kidneys hereditary diseases development united by SRNS symptoms complex. Methods The research included 83 patients (40 girls, 43 boys) aged from 0 up to 16 years with SRNS who undergone molecular genetic testing by next generation sequencing (NGS) with further results validation by Sanger sequencing and bioinformatics analysis by means of the program Alamut. Results Mutations in WT1 gene were revealed in 13 cases (10 girls, 3 boys, mean age — 7,5 years, manifestation mean age — 2 years), four patients have congenital nephrotic syndrome. Revealed morphological variants: focal segmental glomerulosclerosis in 10 cases, minimal changes disease — 3 cases. Pathogenic variants of WT1 gene: 6 missense (c.1217G>A, p.R406K; c.1270A>G, p.K424E; c.1311T>G, p.F437L; c.1399C>T, p.R467W; c.1407C>A, p.D469E; c.1433A>G, p.H478R) and 2 splicing (c.1447+4C>T, c.1447+5G>A) mutations (NM_024426.5 transcript). We revealed two novel variants (c.1217G>A, p.R406K; c.1311T>G, p.F437L) undescribed in HGMD professional database. The most common mutation in WT1 gene is c.1447+5G>A. Mutations in WT1 gene cause various clinical phenotypes: Denys-Drash syndrome (8%), Frasier syndrome (15%), isolated SRNS (77%). All patients with WT1 mutations have significantly lower levels of proteinuria against whole patient cohort, nearly all have sustained hypertension and intermittent hematuria. Conclusion It was established that in 16% of all investigated cases the key factors for the manifestation and progression of SRNS are WT1 gene mutations. Mutations c.1399C>T and c.1433A>G, are associated with rapid progression and early end-stage kidney failure in the age under 6 years.

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