Genetic Testing in Steroid-resistant Nephrotic Syndrome: Why, Who, when and How?

Overview

Journal Pediatr Nephrol

Specialties Nephrology
Pediatrics

Date 2017 Nov 29

PMID 29181713

Citations 54

Authors

Rebecca Preston

Helen M Stuart

Rachel Lennon

Affiliations

Soon will be listed here.

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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References

Wong W . Idiopathic nephrotic syndrome in New Zealand children, demographic, clinical features, initial management and outcome after twelve-month follow-up: results of a three-year national surveillance study. J Paediatr Child Health. 2007; 43(5):337-41. DOI: 10.1111/j.1440-1754.2007.01077.x. View

Faul C, Donnelly M, Merscher-Gomez S, Chang Y, Franz S, Delfgaauw J . The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008; 14(9):931-8. PMC: 4109287. DOI: 10.1038/nm.1857. View

Boyer O, Benoit G, Gribouval O, Nevo F, Tete M, Dantal J . Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011; 22(2):239-45. PMC: 3029896. DOI: 10.1681/ASN.2010050518. View

Karamatic Crew V, Burton N, Kagan A, Green C, Levene C, Flinter F . CD151, the first member of the tetraspanin (TM4) superfamily detected on erythrocytes, is essential for the correct assembly of human basement membranes in kidney and skin. Blood. 2004; 104(8):2217-23. DOI: 10.1182/blood-2004-04-1512. View

Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C . Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome. Am J Hum Genet. 2014; 95(6):637-48. PMC: 4259970. DOI: 10.1016/j.ajhg.2014.10.011. View

Brown E, Pollak M, Barua M . Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int. 2014; 85(5):1030-8. PMC: 4118212. DOI: 10.1038/ki.2014.48. View

Akchurin O, Reidy K . Genetic causes of proteinuria and nephrotic syndrome: impact on podocyte pathobiology. Pediatr Nephrol. 2014; 30(2):221-33. PMC: 4262721. DOI: 10.1007/s00467-014-2753-3. View

Ashraf S, Gee H, Woerner S, Xie L, Vega-Warner V, Lovric S . ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest. 2013; 123(12):5179-89. PMC: 3859425. DOI: 10.1172/JCI69000. View

Wada T, Nangaku M . A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. Clin Kidney J. 2015; 8(6):708-15. PMC: 4655796. DOI: 10.1093/ckj/sfv090. View

10.

Dreyer S, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W . Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in nail patella syndrome. Nat Genet. 1998; 19(1):47-50. DOI: 10.1038/ng0598-47. View

11.

Weber S, Tonshoff B . Recurrence of focal-segmental glomerulosclerosis in children after renal transplantation: clinical and genetic aspects. Transplantation. 2005; 80(1 Suppl):S128-34. DOI: 10.1097/01.tp.0000187110.25512.82. View

12.

Genovese G, Friedman D, Ross M, Lecordier L, Uzureau P, Freedman B . Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science. 2010; 329(5993):841-5. PMC: 2980843. DOI: 10.1126/science.1193032. View

13.

Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M . Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol. 2015; 10(4):592-600. PMC: 4386250. DOI: 10.2215/CJN.06260614. View

14.

Santin S, Bullich G, Tazon-Vega B, Garcia-Maset R, Gimenez I, Silva I . Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011; 6(5):1139-48. PMC: 3087781. DOI: 10.2215/CJN.05260610. View

15.

Barua M, Brown E, Charoonratana V, Genovese G, Sun H, Pollak M . Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int. 2012; 83(2):316-22. PMC: 3647680. DOI: 10.1038/ki.2012.349. View

16.

Dai S, Wang Z, Pan X, Wang W, Chen X, Ren H . Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2009; 25(3):824-35. DOI: 10.1093/ndt/gfp394. View

17.

Ebarasi L, Ashraf S, Bierzynska A, Gee H, McCarthy H, Lovric S . Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet. 2015; 96(1):153-61. PMC: 4289689. DOI: 10.1016/j.ajhg.2014.11.014. View

18.

Trosman J, Weldon C, Douglas M, Kurian A, Kelley R, Deverka P . Payer Coverage for Hereditary Cancer Panels: Barriers, Opportunities, and Implications for the Precision Medicine Initiative. J Natl Compr Canc Netw. 2017; 15(2):219-228. PMC: 5508568. DOI: 10.6004/jnccn.2017.0022. View

19.

Brown E, Schlondorff J, Becker D, Tsukaguchi H, Tonna S, Uscinski A . Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2009; 42(1):72-6. PMC: 2980844. DOI: 10.1038/ng.505. View

20.

Konigshausen E, Sellin L . Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. Biomed Res Int. 2016; 2016:3765608. PMC: 4856884. DOI: 10.1155/2016/3765608. View