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

Maryam Najafi; Korbinian M Riedhammer; Aboulfazl Rad; Paria Najarzadeh Torbati; Riccardo Berutti; Isabel Schüle; Sophie Schroda; Thomas Meitinger; Jasmina Ćomić; Simin Sadeghi Bojd; Tayebeh Baranzehi; Azadeh Shojaei; Anoush Azarfar; Mahmood Reza Khazaei; Anna Köttgen; Rolf Backofen; Ehsan Ghayoor Karimiani; Julia Hoefele; Miriam Schmidts

doi:10.3389/fped.2022.974840

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

Front Pediatr. 2022 Sep 22:10:974840. doi: 10.3389/fped.2022.974840. eCollection 2022.

Authors

Maryam Najafi^{1

2}, Korbinian M Riedhammer^{3

4}, Aboulfazl Rad^{1

5}, Paria Najarzadeh Torbati⁶, Riccardo Berutti³, Isabel Schüle², Sophie Schroda², Thomas Meitinger³, Jasmina Ćomić^{3

4}, Simin Sadeghi Bojd⁷, Tayebeh Baranzehi⁸, Azadeh Shojaei⁹, Anoush Azarfar¹⁰, Mahmood Reza Khazaei¹¹, Anna Köttgen^{12

13}, Rolf Backofen^{13

14}, Ehsan Ghayoor Karimiani^{15

16}, Julia Hoefele³, Miriam Schmidts^{1

2

13}

Affiliations

¹ Genome Research Division, Human Genetics Department, Radboud University Medical Center, Nijmegen, Netherlands.
² Pediatric Genetics Division, Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg University Faculty of Medicine, Freiburg, Germany.
³ Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
⁴ Department of Nephrology, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.
⁵ Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran.
⁶ Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran.
⁷ Children and Adolescents Health Research Center, Research Institute of Cellular and Molecular Science in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
⁸ Department of Biology, University of Sistan and Baluchestan, Zahedan, Iran.
⁹ Department of Medical Genetics and Molecular Biology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
¹⁰ Pediatric Nephrology, Kidney Transplantation Complications Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
¹¹ Department of Pediatrics, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran.
¹² Institute of Genetic Epidemiology, Faculty of Medicine and Medical Center - University of Freiburg, Freiburg, Germany.
¹³ Center for Integrative Biological Signaling Studies, University of Freiburg, Freiburg, Germany.
¹⁴ Bioinformatics Group, Department of Computer Science, University of Freiburg, Freiburg, Germany.
¹⁵ Next Generation Genetic Polyclinic, Mashhad, Iran.
¹⁶ Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London, United Kingdom.

Abstract

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.

Keywords: ARHGDIA; COQ6; Iran; NUP205; SGPL1; SRNS; nephrotic syndrome.