Targeted next-generation sequencing in steroid-resistant nephrotic syndrome : mutations in multiple glomerular genes may influence disease severity
Bullich Vilanova, Gemma (Institut d'Investigació Biomèdica Sant Pau)
Trujillano, Daniel (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Santín, Sheila (Institut d'Investigació Biomèdica Sant Pau)
Ossowski, Stephan (Centre de Regulació Genòmica)
Mendizábal, Santiago (Hospital Universitari i Politècnic La Fe (València))
Fraga Rodríguez, Gloria María (Institut d'Investigació Biomèdica Sant Pau)
Madrid, Alvaro (Hospital Universitari Vall d'Hebron)
Ariceta Iraola, Gema (Hospital Universitari Vall d'Hebron)
Ballarín Castan, José Aurelio (Institut d'Investigació Biomèdica Sant Pau)
Torra Balcells, Roser (Institut d'Investigació Biomèdica Sant Pau)
Estivill, Xavier (Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública)
Ars, Elisabet (Institut d'Investigació Biomèdica Sant Pau)

Date:	2014
Abstract:	Genetic diagnosis of steroid-resistant nephrotic syndrome (SRNS) using Sanger sequencing is complicated by the high genetic heterogeneity and phenotypic variability of this disease. We aimed to improve the genetic diagnosis of SRNS by simultaneously sequencing 26 glomerular genes using massive parallel sequencing and to study whether mutations in multiple genes increase disease severity. High-throughput mutation analysis was performed in 50 SRNS and/or focal segmental glomerulosclerosis (FSGS) patients, a validation cohort of 25 patients with known pathogenic mutations, and a discovery cohort of 25 uncharacterized patients with probable genetic etiology. In the validation cohort, we identified the 42 previously known pathogenic mutations across NPHS1, NPHS2, WT1, TRPC6, and INF2 genes. In the discovery cohort, disease-causing mutations in SRNS/FSGS genes were found in nine patients. We detected three patients with mutations in an SRNS/FSGS gene and COL4A3. Two of them were familial cases and presented a more severe phenotype than family members with mutation in only one gene. In conclusion, our results show that massive parallel sequencing is feasible and robust for genetic diagnosis of SRNS/FSGS. Our results indicate that patients carrying mutations in an SRNS/FSGS gene and also in COL4A3 gene have increased disease severity.
Grants:	Ministerio de Ciencia e Innovación SAF2008-00357 Instituto de Salud Carlos III FIS/FEDER PI11/00733 European Commission 261123 European Commission 262055 Instituto de Salud Carlos III 12/01523 Instituto de Salud Carlos III PI13/01731 Instituto de Salud Carlos III RETIC/REDinREN/RD06/0016 Instituto de Salud Carlos III RETIC/RD012/0021 Agència de Gestió d'Ajuts Universitaris i de Recerca 2009/SGR-1116
Note:	Altres ajuts: Fundación Renal Iñigo Álvarez de Toledo (FRIAT)
Rights:	Tots els drets reservats.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Steroid-resistant nephrotic syndrome ; SRNS ; Genetic diagnosis ; Focal segmental glomerulosclerosis ; FSGS
Published in:	European Journal of Human Genetics, Vol. 23 (november 2014) , p. 1192-1199, ISSN 1476-5438

DOI: 10.1038/ejhg.2014.252
PMID: 25407002

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