Targeted next-generation sequencing in steroid-resistant nephrotic syndrome: mutations in multiple glomerular genes may influence disease severity

• Published in: European journal of human genetics : EJHG 2015-09, Vol.23 (9), p.1192-1199
• Main Authors: Bullich, Gemma, Trujillano, Daniel, Santín, Sheila, Ossowski, Stephan, Mendizábal, Santiago, Fraga, Gloria, Madrid, Álvaro, Ariceta, Gema, Ballarín, José, Torra, Roser, Estivill, Xavier, Ars, Elisabet
• Format: Article
• Language: English
• Subjects: Actinin - genetics; Adolescent; Adult; Autoantigens - genetics; Child; Child, Preschool; Collagen (type IV); Collagen Type IV - genetics; Diagnosis; Etiology; Female; Gene Expression; Genes; Genetic Heterogeneity; Genetic screening; Genetics; Genomics; Genotype; Glomerulosclerosis, Focal Segmental - diagnosis; Glomerulosclerosis, Focal Segmental - genetics; Glomerulosclerosis, Focal Segmental - pathology; High-Throughput Nucleotide Sequencing; Histology; Hospitals; Humans; Infant; Kidney diseases; Laboratories; Male; Microfilament Proteins - genetics; Middle Aged; Mutation; Nephrology; Nephrotic syndrome; Nephrotic Syndrome - congenital; Nephrotic Syndrome - diagnosis; Nephrotic Syndrome - genetics; Nephrotic Syndrome - pathology; Phenotype; Phenotypes; Severity of Illness Index; Transplants & implants; TRPC Cation Channels - genetics; TRPC6 Cation Channel
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/ejhg.2014.252

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.