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

BACKGROUND: Steroid 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 b...

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Autores principales: Najafi, Maryam, Riedhammer, Korbinian M., Rad, Aboulfazl, Torbati, Paria Najarzadeh, Berutti, Riccardo, Schüle, Isabel, Schroda, Sophie, Meitinger, Thomas, Ćomić, Jasmina, Bojd, Simin Sadeghi, Baranzehi, Tayebeh, Shojaei, Azadeh, Azarfar, Anoush, Khazaei, Mahmood Reza, Köttgen, Anna, Backofen, Rolf, Karimiani, Ehsan Ghayoor, Hoefele, Julia, Schmidts, Miriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9555279/
https://www.ncbi.nlm.nih.gov/pubmed/36245711
http://dx.doi.org/10.3389/fped.2022.974840
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author Najafi, Maryam
Riedhammer, Korbinian M.
Rad, Aboulfazl
Torbati, Paria Najarzadeh
Berutti, Riccardo
Schüle, Isabel
Schroda, Sophie
Meitinger, Thomas
Ćomić, Jasmina
Bojd, Simin Sadeghi
Baranzehi, Tayebeh
Shojaei, Azadeh
Azarfar, Anoush
Khazaei, Mahmood Reza
Köttgen, Anna
Backofen, Rolf
Karimiani, Ehsan Ghayoor
Hoefele, Julia
Schmidts, Miriam
author_facet Najafi, Maryam
Riedhammer, Korbinian M.
Rad, Aboulfazl
Torbati, Paria Najarzadeh
Berutti, Riccardo
Schüle, Isabel
Schroda, Sophie
Meitinger, Thomas
Ćomić, Jasmina
Bojd, Simin Sadeghi
Baranzehi, Tayebeh
Shojaei, Azadeh
Azarfar, Anoush
Khazaei, Mahmood Reza
Köttgen, Anna
Backofen, Rolf
Karimiani, Ehsan Ghayoor
Hoefele, Julia
Schmidts, Miriam
author_sort Najafi, Maryam
collection PubMed
description BACKGROUND: Steroid 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 RESULTS: Here, 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. CONCLUSION: In 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.
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spelling pubmed-95552792022-10-13 High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases Najafi, Maryam Riedhammer, Korbinian M. Rad, Aboulfazl Torbati, Paria Najarzadeh Berutti, Riccardo Schüle, Isabel Schroda, Sophie Meitinger, Thomas Ćomić, Jasmina Bojd, Simin Sadeghi Baranzehi, Tayebeh Shojaei, Azadeh Azarfar, Anoush Khazaei, Mahmood Reza Köttgen, Anna Backofen, Rolf Karimiani, Ehsan Ghayoor Hoefele, Julia Schmidts, Miriam Front Pediatr Pediatrics BACKGROUND: Steroid 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 RESULTS: Here, 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. CONCLUSION: In 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. Frontiers Media S.A. 2022-09-22 /pmc/articles/PMC9555279/ /pubmed/36245711 http://dx.doi.org/10.3389/fped.2022.974840 Text en Copyright © 2022 Najafi, Riedhammer, Rad, Torbati, Berutti, Schüle, Schroda, Meitinger, Ćomić, Bojd, Baranzehi, Shojaei, Azarfar, Khazaei, Köttgen, Backofen, Karimiani, Hoefele and Schmidts. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pediatrics
Najafi, Maryam
Riedhammer, Korbinian M.
Rad, Aboulfazl
Torbati, Paria Najarzadeh
Berutti, Riccardo
Schüle, Isabel
Schroda, Sophie
Meitinger, Thomas
Ćomić, Jasmina
Bojd, Simin Sadeghi
Baranzehi, Tayebeh
Shojaei, Azadeh
Azarfar, Anoush
Khazaei, Mahmood Reza
Köttgen, Anna
Backofen, Rolf
Karimiani, Ehsan Ghayoor
Hoefele, Julia
Schmidts, Miriam
High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title_full High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title_fullStr High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title_full_unstemmed High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title_short High detection rate for disease-causing variants in a cohort of 30 Iranian pediatric steroid resistant nephrotic syndrome cases
title_sort high detection rate for disease-causing variants in a cohort of 30 iranian pediatric steroid resistant nephrotic syndrome cases
topic Pediatrics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9555279/
https://www.ncbi.nlm.nih.gov/pubmed/36245711
http://dx.doi.org/10.3389/fped.2022.974840
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