Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome
Authors: Warejko Jillian K. , Tan Weizhen , Daga Ankana , Schapiro David , Lawson Jennifer A. , Shril Shirlee , Lovric Svjetlana , Ashraf Shazia , Rao Jia , Hermle Tobias , Jobst-Schwan Tilman , Widmeier Eugen , Majmundar Amar J. , Schneider Ronen , Gee Heon Yung , Schmidt J. Magdalena , Vivante Asaf , van der Ven Amelie T. , Ityel Hadas , Chen Jing , Sadowski Carolin E. , Kohl Stefan , Pabst Werner L. , Nakayama Makiko , Somers Michael J.G. , Rodig Nancy M. , Daouk Ghaleb , Baum Michelle , Stein Deborah R. , Ferguson Michael A. , Traum Avram Z. , Soliman Neveen A. , Kari Jameela A. , El Desoky Sherif , Fathy Hanan , Zenker Martin , Bakkaloglu Sevcan A. , Müller Dominik , Noyan Aytul , Ozaltin Fatih , Cadnapaphornchai Melissa A. , Hashmi Seema , Hopcian Jeffrey , Kopp Jeffrey B. , Benador Nadine , Bockenhauer Detlef , Bogdanovic Radovan , Stajić Nataša , Chernin Gil , Ettenger Robert , Fehrenbach Henry , Kemper Markus , Munarriz Reyner Loza , Podracka Ludmila , Büscher Rainer , Serdaroglu Erkin , Tasic Velibor , Mane Shrikant , Lifton Richard P. , Braun Daniela A. , Hildebrandt Friedhelm 
Published: November 2017

Background and objectives
Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

Design, setting, participants, & measurements
Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

Results
In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel. NPHS1, PLCE1, NPHS2, and SMARCAL1 were the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

Conclusions
Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.