Clinical genetic testing using a custom-designed steroid-resistant nephrotic syndrome gene panel: analysis and recommendations

Abstract

BackgroundThere are many single-gene causes of steroid-resistant nephrotic syndrome (SRNS) and the list continues to grow rapidly. Prompt comprehensive diagnostic testing is key to realising the clinical benefits of a genetic diagnosis. This report describes a bespoke-designed, targeted next-generation sequencing (NGS) diagnostic gene panel assay to detect variants in 37 genes including the ability to identify copy number variants (CNVs).MethodsThis study reports results of 302 patients referred for SRNS diagnostic gene panel analysis. Phenotype and clinical impact data were collected using a standard proforma. Candidate variants detected by NGS were confirmed by Sanger sequencing/Multiplex Ligation-dependent Probe Amplification with subsequent family segregation analysis where possible.ResultsClinical presentation was nephrotic syndrome in 267 patients and suspected Alport syndrome (AS) in 35. NGS panel testing determined a likely genetic cause of disease in 44/220 (20.0%) paediatric and 10/47 (21.3%) adult nephrotic cases, and 17/35 (48.6%) of haematuria/AS patients. Of 71 patients with genetic disease, 32 had novel pathogenic variants without a previous disease association including two with deletions of one or more exons of NPHS1 or NPHS2.ConclusionGene panel testing provides a genetic diagnosis in a significant number of patients presenting with SRNS or suspected AS. It should be undertaken at an early stage of the care pathway and include the ability to detect CNVs as an emerging mechanism for genes associated with this condition. Use of clinical genetic testing after diagnosis of SRNS has the potential to stratify patients and assist decision-making regarding management.

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

“…17 Previously, multiple targeted disease-specific panel NGS efforts including that of LGMD for molecular diagnostics were performed. 12,[18][19][20][21][22][23][24] But to our knowledge, this study uniquely surpasses them by recruiting a very large number (4656) of patients clinically suspected of a specific disorder (LGMDs) in the USA irrespective of ethnicities. We aimed to provide complete molecular diagnosis to this large group of clinically characterized LGMD patients.…”

Molecular genetic analysis of Steroid Resistant Nephrotic Syndrome: Detection of a novel mutation

“…It is acknowledged that more than 53 genes are associated with SRNS in both recessive and dominant inheritance form (Bierzynska et al 2014;Sen et al 2017). Gemma Bullich et al supposed that genetic testing using standard Sanger methods is costly and time consuming, even if only the most frequently mutated genes are analyzed (Bullich et al 2015) but we think that screening for pathogenic variants in some common genes by this method could be the first cost effective approach.…”

“…Another gene involved in SRNS is FAT1 which Loss of function mutations in this gene results in decreased cell adhesion and migration in fibroblasts and podocytes (Gee et al 2016 Exon 8 and 9 of this gene has been considered as one the most prominent implicated genes in SRNS (Mucha et al 2006;Sen et al 2017). Clinical manifestation of patient 18 showed an affected girl with congenital and sporadic CNS/SRNS.…”

Big data and stratified medicine: what does it mean for children?

“…This has contributed to the development of the gene panel offered by Bristol Genetic Laboratories, which includes 70 genes for nephrotic syndrome in a turnaround time of 6 weeks 23. This has already changed clinical practice, with gene panel testing becoming standard for any newly diagnosed patient, which potentially avoids the need for renal biopsy, as well as avoiding non-specific immunosuppression regimes 24. In addition, combining genomic and clinical profiling of this cohort of children with steroid-resistant nephrotic syndrome has enabled stratification of patients according to aetiology, and hence facilitated appropriate management for individual patients, for example, according to high or low risk for recurrence of disease after renal transplantation 25…”