High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases

Abstract

BackgroundSteroid resistant nephrotic syndrome (SRNS) represents a significant renal disease burden in childhood and adolescence. In contrast to steroid sensitive nephrotic syndrome (SSNS), renal outcomes are significantly poorer in SRNS. Over the past decade, extensive genetic heterogeneity has become evident while disease-causing variants are still only identified in 30% of cases in previously reported studies with proportion and type of variants identified differing depending on the age of onset and ethnical background of probands. A genetic diagnosis however can have implications regarding clinical management, including kidney transplantation, extrarenal disease manifestations, and, in some cases, even causal therapy. Genetic diagnostics therefore play an important role for the clinical care of SRNS affected individuals.Methodology and resultsHere, we performed NPHS2 Sanger sequencing and subsequent exome sequencing in 30 consanguineous Iranian families with a child affected by SRNS with a mean age of onset of 16 months. We identified disease-causing variants and one variant of uncertain significance in 22 families (73%), including variants in NPHS1 (30%), followed by NPHS2 (20%), WT1 (7%) as well as in NUP205, COQ6, ARHGDIA, SGPL1, and NPHP1 in single cases. Eight of these variants have not previously been reported as disease-causing, including four NPHS1 variants and one variant in NPHS2, ARHGDIA, SGPL1, and NPHP1 each.ConclusionIn line with previous studies in non-Iranian subjects, we most frequently identified disease-causing variants in NPHS1 and NPHS2. While Sanger sequencing of NPHS2 can be considered as first diagnostic step in non-congenital cases, the genetic heterogeneity underlying SRNS renders next-generation sequencing based diagnostics as the most efficient genetic screening method. In accordance with the mainly autosomal recessive inheritance pattern, diagnostic yield can be significantly higher in consanguineous than in outbred populations.

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

“…Four different mutations of NUP205 have been described so far to cause FSGS. 7,9,48,49 Braun et al were the first to identify NUP205 and at the same time NUP93 to cause FSGS and they suggested a role of NUP93 in the resistance to oxidative stress and the nuclear shuttling of SMAD. 9 The consequences of NUP205 mutations on nuclear shuttling in podocytes, despite a reduced interaction with NUP93, had not been studied.…”

“…Some NUP205 mutations lead to developmental disorders like abnormal cardiac left-right patterning, some contribute to a variety of neurological diseases, [56][57][58][59] while others lead to SRNS. 13,48,60 This suggest that nucleoporins have explicit roles in specific cell types and that certain cell types react peculiarly to changes in signaling of specific pathways. Strikingly, all those conditions caused by NUP205 mutations are related with YAP/TAZ expression.…”

“…Four different mutations of NUP205 have been described so far to cause FSGS. 7, 9, 48, 49 Braun et al . were the first to identify NUP205 and at the same time NUP93 to cause FSGS and they suggested a role of NUP93 in the resistance to oxidative stress and the nuclear shuttling of SMAD.…”