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

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Abstract

Background

There 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).

Methods

This 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.

Results

Clinical 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.

Conclusion

Gene 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.

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Most cited references 36

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COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

Sema Akman, Friedhelm Hildebrandt, Gianpietro Giorgi … (2011)

Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of end-stage renal failure. Identification of single-gene causes of SRNS has generated some insights into its pathogenesis; however, additional genes and disease mechanisms remain obscure, and SRNS continues to be treatment refractory. Here we have identified 6 different mutations in coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) in 13 individuals from 7 families by homozygosity mapping. Each mutation was linked to early-onset SRNS with sensorineural deafness. The deleterious effects of these human COQ6 mutations were validated by their lack of complementation in coq6-deficient yeast. Furthermore, knockdown of Coq6 in podocyte cell lines and coq6 in zebrafish embryos caused apoptosis that was partially reversed by coenzyme Q10 treatment. In rats, COQ6 was located within cell processes and the Golgi apparatus of renal glomerular podocytes and in stria vascularis cells of the inner ear, consistent with an oto-renal disease phenotype. These data suggest that coenzyme Q10-related forms of SRNS and hearing loss can be molecularly identified and potentially treated.

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Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

Agnes Trautmann, Monica Bodria, Fatih Ozaltin … (2015)

Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome.

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Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

Agnieszka Bierzynska, Hugh McCarthy, Katrina Soderquest … (2017)

Steroid Resistant Nephrotic Syndrome (SRNS) in children and young adults has differing etiologies with monogenic disease accounting for 2.9-30% in selected series. Using whole exome sequencing we sought to stratify a national population of children with SRNS into monogenic and non-monogenic forms, and further define those groups by detailed phenotypic analysis. Pediatric patients with SRNS were identified via a national United Kingdom Renal Registry. Whole exome sequencing was performed on 187 patients, of which 12% have a positive family history with a focus on the 53 genes currently known to be associated with nephrotic syndrome. Genetic findings were correlated with individual case disease characteristics. Disease causing variants were detected in 26.2% of patients. Most often this occurred in the three most common SRNS-associated genes: NPHS1, NPHS2, and WT1 but also in 14 other genes. The genotype did not always correlate with expected phenotype since mutations in OCRL, COL4A3, and DGKE associated with specific syndromes were detected in patients with isolated renal disease. Analysis by primary/presumed compared with secondary steroid resistance found 30.8% monogenic disease in primary compared with none in secondary SRNS permitting further mechanistic stratification. Genetic SRNS progressed faster to end stage renal failure, with no documented disease recurrence post-transplantation within this cohort. Primary steroid resistance in which no gene mutation was identified had a 47.8% risk of recurrence. In this unbiased pediatric population, whole exome sequencing allowed screening of all current candidate genes. Thus, deep phenotyping combined with whole exome sequencing is an effective tool for early identification of SRNS etiology, yielding an evidence-based algorithm for clinical management.

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Author and article information

Journal

Journal ID (nlm-ta): J Med Genet

Journal ID (iso-abbrev): J. Med. Genet

Journal ID (hwp): jmedgenet

Journal ID (publisher-id): jmg

Title: Journal of Medical Genetics

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Print): 0022-2593

ISSN (Electronic): 1468-6244

Publication date (Print): December 2017

Publication date (Electronic): 5 August 2017

Volume: 54

Issue: 12

Pages: 795-804

Affiliations

[1 ] departmentBristol Renal , School of Clinical Sciences, University of Bristol , Bristol, UK

[2 ] Bristol Royal Hospital for Children , Bristol, UK

[3 ] Bristol Genetics Laboratory, Southmead Hospital , Bristol, UK

Author notes

[Correspondence to ] Professor Moin A Saleem, Bristol Renal, School of Clinical Sciences, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY; M.Saleem@ 123456bristol.ac.uk

Article

Publisher ID: jmedgenet-2017-104811

DOI: 10.1136/jmedgenet-2017-104811

PMC ID: 5740557

PubMed ID: 28780565

SO-VID: ab4dc98a-28c2-4c57-b82a-06e415bf78b7

License:

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

History

Date received : 15 May 2017

Date revision received : 27 June 2017

Date accepted : 29 June 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000659, Research Trainees Coordinating Centre;

Funded by: FundRef http://dx.doi.org/10.13039/501100000291, Kidney Research UK;

Funded by: FundRef http://dx.doi.org/10.13039/501100000405, Kids Kidney Research;

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ScienceOpen disciplines: Genetics

Keywords: podocyte,steroid-resistant nephrotic syndrome,next generation sequencing,alport syndrome,gene panel testing,srns,focal segmental glomerulosclerosis,fsgs

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ScienceOpen disciplines: Genetics

Keywords: podocyte, steroid-resistant nephrotic syndrome, next generation sequencing, alport syndrome, gene panel testing, srns, focal segmental glomerulosclerosis, fsgs

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

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Most cited references 36

COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness.

Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort.

Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management.

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