Warejko, JK; Tan, W; Daga, A; Schapiro, D; Lawson, JA; Shril, S; Lovric, S; ... Hildebrandt, F; + view all Warejko, JK; Tan, W; Daga, A; Schapiro, D; Lawson, JA; Shril, S; Lovric, S; Ashraf, S; Rao, J; Hermle, T; Jobst-Schwan, T; Widmeier, E; Majmundar, AJ; Schneider, R; Gee, HY; Schmidt, JM; Vivante, A; van der Ven, AT; Ityel, H; Chen, J; Sadowski, CE; Kohl, S; Pabst, WL; Nakayama, M; Somers, MJG; Rodig, NM; Daouk, G; Baum, M; Stein, DR; Ferguson, MA; Traum, AZ; Soliman, NA; Kari, JA; El Desoky, S; Fathy, H; Zenker, M; Bakkaloglu, SA; Mueller, D; Noyan, A; Ozaltin, F; Cadnapaphornchai, MA; Hashmi, S; Hopcian, J; Kopp, JB; Benador, N; Bockenhauer, D; Bogdanovic, R; Stajic, N; Chernin, G; Ettenger, R; Fehrenbach, H; Kemper, M; Munarriz, RL; Podracka, L; Buscher, R; Serdaroglu, E; Tasic, V; Mane, S; Lifton, RP; Braun, DA; Hildebrandt, F; - view fewer (2018) Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome. Clinical Journal of the American Society of Nephrology , 13 (1) pp. 53-62. 10.2215/CJN.04120417.

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Abstract

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, PARTIIPANTS AND 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.

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