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