Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

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, Johanna Magdalena; Vivante, Asaf; Ven, Amelie T. van der; Ityel, Hadas; Chen, Jing; Sadowski, Carolin E.; Kohl, Stefan; Pabst, Werner L.; Nakayama, Makiko; Somers, Michael J.; Rodig, Nancy; Daouk, Ghaleb H.; Baum, Michelle A.; Stein, Deborah R.; Ferguson, Michael; Traum, Avram Z.; Soliman, Neveen A.; Kari, Jameela A.; Desoky, Sherif El; Fathy, Hanan; Zenker, Martin; Bakkaloğlu, Sevcan A.; Müller, Dominik; Noyan, Aytül; Özaltın, Fatih; Cadnapaphornchai, Melissa A.; Hashmi, Seema; Hopcian, Jeffrey; Kopp, Jeffrey B.; Benador, Nadine; Böckenhauer, Detlef; Bogdanović, Radovan; Stajić, Nataša; Chernin, Gil; Ettenger, Robert B.; Fehrenbach, Henry; Kemper, Markus J.; Munárriz, Reyner Loza; Podracká, Ľudmila; Büscher, Rainer; Serdaroğlu, Erkin; Tasić, Velibor; Mane, Shrikant; Lifton, Richard P.; Braun, Daniela A.; Hildebrandt, Friedhelm

doi:10.2215/cjn.04120417

Cited by 179 publications

(181 citation statements)

References 31 publications

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“…In our cohort, the genetic diagnostic rate was 32.1% among patients with SRNS which is similar to the previous reports from the international pediatric cohort of SRNS. 10,11 The subgroup of SRNS in this study included 1/3 cases of early-onset age group. In the other cohorts, the fraction of detecting single-gene causation in SRNS is inversely correlated to the age of manifestation.…”

Section: Discussionmentioning

confidence: 99%

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

et al. 2019

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To explore the approaches and diagnostic yield of genetic testing for renal disease in children, we describe the genotype and phenotype of the national cohort of children with renal disease from 13 different regions of China recruited from 2014 to 2018 by building up the multicenter registration system (Chinese Children Genetic Kidney Disease Database, CCGKDD). Genetic diagnosis was confirmed in 42.1% of our cohort of 1001 pediatric patients with clinical suspicion of a genetic renal disease. Of the 106 distinct monogenetic disorders detected, 15 accounted for 60.7% of genetic diagnoses. The diagnostic yield was 29.1% in steroid resistant nephritic syndrome (SRNS), 61.4% in cystic renal disease, 17.0% in congenital anomalies of the kidney and urinary tract (CAKUT), 62.3% in renal tubular disease/renal calcinosis, and 23.9% for chronic kidney disease (CKD) 3 to 5 stage with unknown origin. Genetic approaches of target gene sequence (TGS), singleton whole‐exome sequencing (WES) and trio‐WES were performed with diagnostic rates of 44.8%, 36.2%, and 42.6%, respectively. The early use of trio‐WES could improve the diagnostic rate especially in renal tubular disease and calcinosis. We report the genetic spectrum of Chinese children with renal disease. Establishment of the CCGKDD will improve the genetic work on renal disease.

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Section: Discussionmentioning

confidence: 99%

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

et al. 2019

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“…To assess the applicability of kidney organoids from different iPSC lines for the study of genetic kidney diseases (Cruz et al, 2017b;Forbes et al, 2018b;Tanigawa et al, 2018a), we determined the expression of genes causing congenital anomalies of the kidney and urinary tract (CAKUT), hereditary renal cystic (HRC) diseases and hereditary tumor syndromes (Brown et al, 2014;Hildebrandt, 2010;Vivante and Hildebrandt, 2016;Warejko et al, 2018) (Fig. 5A,B, Supplementary Fig.…”

Section: Genes Associated With Kidney Diseases Are Expressed In Expecmentioning

confidence: 99%

Kidney organoid reproducibility across multiple human iPSC lines and diminished off target cells after transplantation revealed by single cell transcriptomics

Subramanian

Sidhom

Emani

et al. 2019

Preprint

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Human iPSC-derived kidney organoids have the potential to revolutionize discovery, but assessing their consistency and reproducibility across iPSC lines, and reducing the generation of off-target cells remain an open challenge. Here, we used single cell RNA-Seq (scRNA-Seq) to profile 415,775 cells to show that organoid composition and development are comparable to human fetal and adult kidneys. Although cell classes were largely reproducible across iPSC lines, time points, protocols, and replicates, cell proportions were variable between different iPSC lines. Off-target cell proportions were the most variable. Prolonged in vitro culture did not alter cell types, but organoid transplantation under the mouse kidney capsule diminished offtarget cells. Our work shows how scRNA-seq can help score organoids for reproducibility, faithfulness and quality, that kidney organoids derived from different iPSC lines are comparable surrogates for human kidney, and that transplantation enhances their formation by diminishing off-target cells.

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“…In fact, it has been shown that a monogenic disease-causing mutation in one of approximately 220 genes can be identified in up to 20% of patients who develop CKD before 25 years of age. 2 Specifically, a monogenic cause can be identified in 5%-14% of patients with CAKUT, 3-5 11%-30% of patients with SRNS, [6][7][8][9][10] 14% of patients with chronic GN, 11 33%-63% of patients with a renal cystic ciliopathy, [12][13][14][15] and 15%-29% of patients with urinary stone disease. [16][17][18][19] This has important implications for the clinical management of children and young adults with CKD.…”

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confidence: 99%

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

Mann¹,

Braun²,

Amann³

et al. 2019

JASN

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113

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Background Whole-exome sequencing (WES) finds a CKD-related mutation in approximately 20% of patients presenting with CKD before 25 years of age. Although provision of a molecular diagnosis could have important implications for clinical management, evidence is lacking on the diagnostic yield and clinical utility of WES for pediatric renal transplant recipients. Methods To determine the diagnostic yield of WES in pediatric kidney transplant recipients, we recruited 104 patients who had received a transplant at Boston Children's Hospital from 2007 through 2017, performed WES, and analyzed results for likely deleterious variants in approximately 400 genes known to cause CKD. Results By WES, we identified a genetic cause of CKD in 34 out of 104 (32.7%) transplant recipients. The likelihood of detecting a molecular genetic diagnosis was highest for patients with urinary stone disease (three out of three individuals), followed by renal cystic ciliopathies (seven out of nine individuals), steroidresistant nephrotic syndrome (nine out of 21 individuals), congenital anomalies of the kidney and urinary tract (ten out of 55 individuals), and chronic glomerulonephritis (one out of seven individuals). WES also yielded a molecular diagnosis for four out of nine individuals with ESRD of unknown etiology. The WESrelated molecular genetic diagnosis had implications for clinical care for five patients. Conclusions Nearly one third of pediatric renal transplant recipients had a genetic cause of their kidney disease identified by WES. Knowledge of this genetic information can help guide management of both transplant patients and potential living related donors.

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Whole Exome Sequencing of Patients with Steroid-Resistant Nephrotic Syndrome

Cited by 179 publications

References 31 publications

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

Genetic spectrum of renal disease for 1001 Chinese children based on a multicenter registration system

Kidney organoid reproducibility across multiple human iPSC lines and diminished off target cells after transplantation revealed by single cell transcriptomics

Whole-Exome Sequencing Enables a Precision Medicine Approach for Kidney Transplant Recipients

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