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Open Access 01-02-2019 | Review

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Authors: Rebecca Preston, Helen M. Stuart, Rachel Lennon

Published in: Pediatric Nephrology | Issue 2/2019

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.

Wong W (2007) 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 43:337–341PubMed

Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J (2003) Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis 42:1107–1113PubMed

Smith JM, Stablein DM, Munoz R, Hebert D, McDonald RA (2007) Contributions of the transplant registry: the 2006 annual report of the north American Pediatric renal trials and collaborative studies (NAPRTCS). Pediatr Transplant 11:366–373PubMed

Benoit G, Machuca E, Antignac C (2010) Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations. Pediatr Nephrol 25:1621–1632PubMedPubMedCentral

McCarthy HJ, Saleem MA (2011) Genetics in clinical practice: nephrotic and proteinuric syndromes. Nephron Exp Nephrol 118:e1–e8PubMed

Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L, Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E, Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M, Romagnani P (2015) Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol 26:230–236PubMed

Hildebrandt F (2010) Genetic kidney diseases. Lancet 375:1287–1295PubMedPubMedCentral

Bierzynska A, McCarthy HJ, Soderquest K, Sen ES, Colby E, Ding WY, Nabhan MM, Kerecuk L, Hegde S, Hughes D, Marks S, Feather S, Jones C, Webb NJ, Ognjanovic M, Christian M, Gilbert RD, Sinha MD, Lord GM, Simpson M, Koziell AB, Welsh GI, Saleem MA (2017) Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 91:937–947PubMed

Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, SRNS Study Group, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289PubMed

10.

Wang F, Zhang Y, Mao J, Yu Z, Yi Z, Yu L, Sun J, Wei X, Ding F, Zhang H, Xiao H, Yao Y, Tan W, Lovric S, Ding J, Hildebrandt F (2017) Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 32:1181–1192PubMedPubMedCentral

11.

Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 1:575–582PubMed

12.

Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354PubMed

13.

Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O'Toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405PubMed

14.

Lowik MM, Groenen PJ, Pronk I, Lilien MR, Goldschmeding R, Dijkman HB, Levtchenko EN, Monnens LA, van den Heuvel LP (2007) Focal segmental glomerulosclerosis in a patient homozygous for a CD2AP mutation. Kidney Int 72:1198–1203PubMed

15.

Winn MP, Conlon PJ, Lynn KL, Farrington MK, Creazzo T, Hawkins AF, Daskalakis N, Kwan SY, Ebersviller S, Burchette JL, Pericak-Vance MA, Howell DN, Vance JM, Rosenberg PB (2005) A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science 308:1801–1804PubMed

16.

Ebarasi L, Ashraf S, Bierzynska A, Gee HY, McCarthy HJ, Lovric S, Sadowski CE, Pabst W, Vega-Warner V, Fang H, Koziell A, Simpson MA, Dursun I, Serdaroglu E, Levy S, Saleem MA, Hildebrandt F, Majumdar A (2015) Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet 96:153–161PubMedPubMedCentral

17.

Gee HY, Sadowski CE, Aggarwal PK, Porath JD, Yakulov TA, Schueler M, Lovric S, Ashraf S, Braun DA, Halbritter J, Fang H, Airik R, Vega-Warner V, Cho KJ, Chan TA, Morris LG, Ffrench-Constant C, Allen N, McNeill H, Buscher R, Kyrieleis H, Wallot M, Gaspert A, Kistler T, Milford DV, Saleem MA, Keng WT, Alexander SI, Valentini RP, Licht C, Teh JC, Bogdanovic R, Koziell A, Bierzynska A, Soliman NA, Otto EA, Lifton RP, Holzman LB, Sibinga NE, Walz G, Tufro A, Hildebrandt F (2016) FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun 7:10822PubMedPubMedCentral

18.

Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470PubMed

19.

Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D (1991) Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys–Drash syndrome. Cell 67:437–447PubMed

20.

Dreyer SD, Zhou G, Baldini A, Winterpacht A, Zabel B, Cole W, Johnson RL, Lee B (1998) Mutations in LMX1B cause abnormal skeletal patterning and renal dysplasia in Nail Patella syndrome. Nat Genet 19:47–50PubMed

21.

Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, Andre JL, Bogdanovic R, Burguet A, Cockfield S, Cordeiro I, Frund S, Illies F, Joseph M, Kaitila I, Lama G, Loirat C, McLeod DR, Milford DV, Petty EM, Rodrigo F, Saraiva JM, Schmidt B, Smith GC, Spranger J, Stein A, Thiele H, Tizard J, Weksberg R, Lupski JR, Stockton DW (2002) Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Nat Genet 30:215–220PubMed

22.

Braun DA, Sadowski CE, Kohl S, Lovric S, Astrinidis SA, Pabst WL, Gee HY, Ashraf S, Lawson JA, Shril S, Airik M, Tan W, Schapiro D, Rao J, Choi WI, Hermle T, Kemper MJ, Pohl M, Ozaltin F, Konrad M, Bogdanovic R, Buscher R, Helmchen U, Serdaroglu E, Lifton RP, Antonin W, Hildebrandt F (2016) Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome. Nat Genet 48:457–465PubMedPubMedCentral

23.

Miyake N, Tsukaguchi H, Koshimizu E, Shono A, Matsunaga S, Shiina M, Mimura Y, Imamura S, Hirose T, Okudela K, Nozu K, Akioka Y, Hattori M, Yoshikawa N, Kitamura A, Cheong HI, Kagami S, Yamashita M, Fujita A, Miyatake S, Tsurusaki Y, Nakashima M, Saitsu H, Ohashi K, Imamoto N, Ryo A, Ogata K, Iijima K, Matsumoto N (2015) Biallelic mutations in nuclear pore complex subunit NUP107 cause early-childhood-onset steroid-resistant Nephrotic syndrome. Am J Hum Genet 97:555–566PubMedPubMedCentral

24.

Izu A, Yanagida H, Sugimoto K, Fujita S, Sakata N, Wada N, Okada M, Takemura T (2011) Pathogenesis of focal segmental glomerular sclerosis in a girl with the partial deletion of chromosome 6p. Tohoku J Exp Med 223:187–192PubMed

25.

Esposito T, Lea RA, Maher BH, Moses D, Cox HC, Magliocca S, Angius A, Nyholt DR, Titus T, Kay T, Gray NA, Rastaldi MP, Parnham A, Gianfrancesco F, Griffiths LR (2013) Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene. Hum Mol Genet 22:3654–3666PubMed

26.

Kerti A, Csohany R, Wagner L, Javorszky E, Maka E, Tory K (2013) NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis. Pediatr Nephrol 28:2061–2064PubMed

27.

Thong KM, Xu Y, Cook J, Takou A, Wagner B, Kawar B, Ong AC (2013) Cosegregation of focal segmental glomerulosclerosis in a family with familial partial lipodystrophy due to a mutation in LMNA. Nephron Clin Pract 124:31–37PubMed

28.

Colin E, Huynh Cong E, Mollet G, Guichet A, Gribouval O, Arrondel C, Boyer O, Daniel L, Gubler MC, Ekinci Z, Tsimaratos M, Chabrol B, Boddaert N, Verloes A, Chevrollier A, Gueguen N, Desquiret-Dumas V, Ferre M, Procaccio V, Richard L, Funalot B, Moncla A, Bonneau D, Antignac C (2014) Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway–Mowat syndrome. Am J Hum Genet 95:637–648PubMedPubMedCentral

29.

Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256PubMed

30.

Kopp JB, Smith MW, Nelson GW, Johnson RC, Freedman BI, Bowden DW, Oleksyk T, McKenzie LM, Kajiyama H, Ahuja TS, Berns JS, Briggs W, Cho ME, Dart RA, Kimmel PL, Korbet SM, Michel DM, Mokrzycki MH, Schelling JR, Simon E, Trachtman H, Vlahov D, Winkler CA (2008) MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat Genet 40:1175–1184PubMedPubMedCentral

31.

Boyer O, Benoit G, Gribouval O, Nevo F, Tete MJ, Dantal J, Gilbert-Dussardier B, Touchard G, Karras A, Presne C, Grunfeld JP, Legendre C, Joly D, Rieu P, Mohsin N, Hannedouche T, Moal V, Gubler MC, Broutin I, Mollet G, Antignac C (2011) Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol 22:239–245PubMedPubMedCentral

32.

Mele C, Iatropoulos P, Donadelli R, Calabria A, Maranta R, Cassis P, Buelli S, Tomasoni S, Piras R, Krendel M, Bettoni S, Morigi M, Delledonne M, Pecoraro C, Abbate I, Capobianchi MR, Hildebrandt F, Otto E, Schaefer F, Macciardi F, Ozaltin F, Emre S, Ibsirlioglu T, Benigni A, Remuzzi G, Noris M, PodoNet Consortium (2011) MYO1E mutations and childhood familial focal segmental glomerulosclerosis. N Engl J Med 365:295–306PubMedPubMedCentral

33.

Bierzynska A, Soderquest K, Dean P, Colby E, Rollason R, Jones C, Inward CD, McCarthy HJ, Simpson MA, Lord GM, Williams M, Welsh GI, Koziell AB, Saleem MA, NephroS, UK study of Nephrotic Syndrome (2017) MAGI2 mutations cause congenital Nephrotic syndrome. J Am Soc Nephrol 28:1614–1621PubMed

34.

Gbadegesin RA, Hall G, Adeyemo A, Hanke N, Tossidou I, Burchette J, Wu G, Homstad A, Sparks MA, Gomez J, Jiang R, Alonso A, Lavin P, Conlon P, Korstanje R, Stander MC, Shamsan G, Barua M, Spurney R, Singhal PC, Kopp JB, Haller H, Howell D, Pollak MR, Shaw AS, Schiffer M, Winn MP (2014) Mutations in the gene that encodes the F-actin binding protein anillin cause FSGS. J Am Soc Nephrol 25:1991–2002PubMedPubMedCentral

35.

Akilesh S, Suleiman H, Yu H, Stander MC, Lavin P, Gbadegesin R, Antignac C, Pollak M, Kopp JB, Winn MP, Shaw AS (2011) Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest 121:4127–4137PubMedPubMedCentral

36.

Gee HY, Saisawat P, Ashraf S, Hurd TW, Vega-Warner V, Fang H, Beck BB, Gribouval O, Zhou W, Diaz KA, Natarajan S, Wiggins RC, Lovric S, Chernin G, Schoeb DS, Ovunc B, Frishberg Y, Soliman NA, Fathy HM, Goebel H, Hoefele J, Weber LT, Innis JW, Faul C, Han Z, Washburn J, Antignac C, Levy S, Otto EA, Hildebrandt F (2013) ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest 123:3243–3253PubMedPubMedCentral

37.

Gee HY, Zhang F, Ashraf S, Kohl S, Sadowski CE, Vega-Warner V, Zhou W, Lovric S, Fang H, Nettleton M, Zhu JY, Hoefele J, Weber LT, Podracka L, Boor A, Fehrenbach H, Innis JW, Washburn J, Levy S, Lifton RP, Otto EA, Han Z, Hildebrandt F (2015) KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. J Clin Invest 125:2375–2384PubMedPubMedCentral

38.

Dai S, Wang Z, Pan X, Wang W, Chen X, Ren H, Hao C, Han B, Chen N (2010) Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis. Nephrol Dial Transplant 25:824–835PubMed

39.

Ozaltin F, Ibsirlioglu T, Taskiran EZ, Baydar DE, Kaymaz F, Buyukcelik M, Kilic BD, Balat A, Iatropoulos P, Asan E, Akarsu NA, Schaefer F, Yilmaz E, Bakkaloglu A, PodoNet Consortium (2011) Disruption of PTPRO causes childhood-onset nephrotic syndrome. Am J Hum Genet 89:139–147PubMedPubMedCentral

40.

Gee HY, Ashraf S, Wan X, Vega-Warner V, Esteve-Rudd J, Lovric S, Fang H, Hurd TW, Sadowski CE, Allen SJ, Otto EA, Korkmaz E, Washburn J, Levy S, Williams DS, Bakkaloglu SA, Zolotnitskaya A, Ozaltin F, Zhou W, Hildebrandt F (2014) Mutations in EMP2 cause childhood-onset nephrotic syndrome. Am J Hum Genet 94:884–890PubMedPubMedCentral

41.

Genovese G, Friedman DJ, Ross MD, Lecordier L, Uzureau P, Freedman BI, Bowden DW, Langefeld CD, Oleksyk TK, Uscinski Knob AL, Bernhardy AJ, Hicks PJ, Nelson GW, Vanhollebeke B, Winkler CA, Kopp JB, Pays E, Pollak MR (2010) Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329:841–845PubMedPubMedCentral

42.

Ovunc B, Otto EA, Vega-Warner V, Saisawat P, Ashraf S, Ramaswami G, Fathy HM, Schoeb D, Chernin G, Lyons RH, Yilmaz E, Hildebrandt F (2011) Exome sequencing reveals cubilin mutation as a single-gene cause of proteinuria. J Am Soc Nephrol 22:1815–1820PubMedPubMedCentral

43.

Barua M, Shieh E, Schlondorff J, Genovese G, Kaplan BS, Pollak MR (2014) Exome sequencing and in vitro studies identified podocalyxin as a candidate gene for focal and segmental glomerulosclerosis. Kidney Int 85:124–133PubMed

44.

Zenker M, Aigner T, Wendler O, Tralau T, Muntefering H, Fenski R, Pitz S, Schumacher V, Royer-Pokora B, Wuhl E, Cochat P, Bouvier R, Kraus C, Mark K, Madlon H, Dotsch J, Rascher W, Maruniak-Chudek I, Lennert T, Neumann LM, Reis A (2004) Human laminin beta2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Hum Mol Genet 13:2625–2632PubMed

45.

Kambham N, Tanji N, Seigle RL, Markowitz GS, Pulkkinen L, Uitto J, D'Agati VD (2000) Congenital focal segmental glomerulosclerosis associated with beta4 integrin mutation and epidermolysis bullosa. Am J Kidney Dis 36:190–196PubMed

46.

Has C, Sparta G, Kiritsi D, Weibel L, Moeller A, Vega-Warner V, Waters A, He Y, Anikster Y, Esser P, Straub BK, Hausser I, Bockenhauer D, Dekel B, Hildebrandt F, Bruckner-Tuderman L, Laube GF (2012) Integrin alpha3 mutations with kidney, lung, and skin disease. N Engl J Med 366:1508–1514PubMedPubMedCentral

47.

Voskarides K, Damianou L, Neocleous V, Zouvani I, Christodoulidou S, Hadjiconstantinou V, Ioannou K, Athanasiou Y, Patsias C, Alexopoulos E, Pierides A, Kyriacou K, Deltas C (2007) COL4A3/COL4A4 mutations producing focal segmental glomerulosclerosis and renal failure in thin basement membrane nephropathy. J Am Soc Nephrol 18:3004–3016PubMed

48.

Okamoto K, Tokunaga K, Doi K, Fujita T, Suzuki H, Katoh T, Watanabe T, Nishida N, Mabuchi A, Takahashi A, Kubo M, Maeda S, Nakamura Y, Noiri E (2011) Common variation in GPC5 is associated with acquired nephrotic syndrome. Nat Genet 43:459–463PubMed

49.

Karamatic Crew V, Burton N, Kagan A, Green CA, Levene C, Flinter F, Brady RL, Daniels G, Anstee DJ (2004) 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 104:2217–2223PubMed

50.

Salviati L, Sacconi S, Murer L, Zacchello G, Franceschini L, Laverda AM, Basso G, Quinzii C, Angelini C, Hirano M, Naini AB, Navas P, DiMauro S, Montini G (2005) Infantile encephalomyopathy and nephropathy with CoQ10 deficiency: a CoQ10-responsive condition. Neurology 65:606–608PubMed

51.

Heeringa SF, Chernin G, Chaki M, Zhou W, Sloan AJ, Ji Z, Xie LX, Salviati L, Hurd TW, Vega-Warner V, Killen PD, Raphael Y, Ashraf S, Ovunc B, Schoeb DS, McLaughlin HM, Airik R, Vlangos CN, Gbadegesin R, Hinkes B, Saisawat P, Trevisson E, Doimo M, Casarin A, Pertegato V, Giorgi G, Prokisch H, Rotig A, Nurnberg G, Becker C, Wang S, Ozaltin F, Topaloglu R, Bakkaloglu A, Bakkaloglu SA, Muller D, Beissert A, Mir S, Berdeli A, Varpizen S, Zenker M, Matejas V, Santos-Ocana C, Navas P, Kusakabe T, Kispert A, Akman S, Soliman NA, Krick S, Mundel P, Reiser J, Nurnberg P, Clarke CF, Wiggins RC, Faul C, Hildebrandt F (2011) COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J Clin Invest 121:2013–2024PubMedPubMedCentral

52.

Lopez LC, Schuelke M, Quinzii CM, Kanki T, Rodenburg RJ, Naini A, Dimauro S, Hirano M (2006) Leigh syndrome with nephropathy and CoQ10 deficiency due to decaprenyl diphosphate synthase subunit 2 (PDSS2) mutations. Am J Hum Genet 79:1125–1129PubMedPubMedCentral

53.

Ashraf S, Gee HY, Woerner S, Xie LX, Vega-Warner V, Lovric S, Fang H, Song X, Cattran DC, Avila-Casado C, Paterson AD, Nitschke P, Bole-Feysot C, Cochat P, Esteve-Rudd J, Haberberger B, Allen SJ, Zhou W, Airik R, Otto EA, Barua M, Al-Hamed MH, Kari JA, Evans J, Bierzynska A, Saleem MA, Bockenhauer D, Kleta R, El Desoky S, Hacihamdioglu DO, Gok F, Washburn J, Wiggins RC, Choi M, Lifton RP, Levy S, Han Z, Salviati L, Prokisch H, Williams DS, Pollak M, Clarke CF, Pei Y, Antignac C, Hildebrandt F (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179–5189PubMedPubMedCentral

54.

Yasukawa T, Suzuki T, Ueda T, Ohta S, Watanabe K (2000) Modification defect at anticodon wobble nucleotide of mitochondrial tRNAs(Leu)(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J Biol Chem 275:4251–4257PubMed

55.

Berkovic SF, Dibbens LM, Oshlack A, Silver JD, Katerelos M, Vears DF, Lullmann-Rauch R, Blanz J, Zhang KW, Stankovich J, Kalnins RM, Dowling JP, Andermann E, Andermann F, Faldini E, D'Hooge R, Vadlamudi L, Macdonell RA, Hodgson BL, Bayly MA, Savige J, Mulley JC, Smyth GK, Power DA, Saftig P, Bahlo M (2008) Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis. Am J Hum Genet 82:673–684PubMedPubMedCentral

56.

Kaneko K, Hasui M, Hata A, Hata D, Nozu K (2010) Focal segmental glomerulosclerosis in a boy with Dent-2 disease. Pediatr Nephrol 25:781–782PubMed

57.

Agarwal AK, Zhou XJ, Hall RK, Nicholls K, Bankier A, Van Esch H, Fryns JP, Garg A (2006) Focal segmental glomerulosclerosis in patients with mandibuloacral dysplasia owing to ZMPSTE24 deficiency. J Investig Med 54:208–213PubMed

58.

van der Knaap MS, Wevers RA, Monnens L, Jakobs C, Jaeken J, van Wijk JA (1996) Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome. J Inherit Metab Dis 19:787–791PubMed

59.

Kranz C, Denecke J, Lehle L, Sohlbach K, Jeske S, Meinhardt F, Rossi R, Gudowius S, Marquardt T (2004) Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I. Am J Hum Genet 74:545–551PubMedPubMedCentral

60.

Huynh Cong E, Bizet AA, Boyer O, Woerner S, Gribouval O, Filhol E, Arrondel C, Thomas S, Silbermann F, Canaud G, Hachicha J, Ben Dhia N, Peraldi MN, Harzallah K, Iftene D, Daniel L, Willems M, Noel LH, Bole-Feysot C, Nitschke P, Gubler MC, Mollet G, Saunier S, Antignac C (2014) A homozygous missense mutation in the ciliary gene TTC21B causes familial FSGS. J Am Soc Nephrol 25:2435–2443PubMed

61.

Sethi S, Fervenza FC, Zhang Y, Smith RJ (2012) Secondary focal and segmental glomerulosclerosis associated with single-nucleotide polymorphisms in the genes encoding complement factor H and C3. Am J Kidney Dis 60:316–321PubMedPubMedCentral

62.

Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang C, Chen P, Lu D, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M (2013) DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol 24:377–384PubMed

63.

Conlon PJ, Lynn K, Winn MP, Quarles LD, Bembe ML, Pericak-Vance M, Speer M, Howell DN (1999) Spectrum of disease in familial focal and segmental glomerulosclerosis. Kidney Int 56:1863–1871PubMed

64.

Akchurin O, Reidy KJ (2015) Genetic causes of proteinuria and nephrotic syndrome: impact on podocyte pathobiology. Pediatr Nephrol 30:221–233PubMed

65.

Santin S, Bullich G, Tazon-Vega B, Garcia-Maset R, Gimenez I, Silva I, Ruiz P, Ballarin J, Torra R, Ars E (2011) Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6:1139–1148PubMedPubMedCentral

66.

Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F, Arbeitsgemeinschaft fur Paediatrische Nephrologie Study Group (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:e907–e919PubMed

67.

Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, Scambler P (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 11:379–388PubMed

68.

Santin S, Tazon-Vega B, Silva I, Cobo MA, Gimenez I, Ruiz P, Garcia-Maset R, Ballarin J, Torra R, Ars E, FSGS Spanish Study Group (2011) Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 6:344–354PubMedPubMedCentral

69.

Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C (2004) NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66:571–579PubMed

70.

Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S, Wada N, Takahashi Y, Kaku Y, Satomura K, Ikeda M, Honda M, Iijima K, Yoshikawa N (2005) Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney Int 67:1248–1255PubMed

71.

Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tete MJ, Loirat C, Dantal J, Fischbach M, Pouteil-Noble C, Decramer S, Hoehne M, Benzing T, Charbit M, Niaudet P, Antignac C (2008) Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. J Am Soc Nephrol 19:1871–1878PubMedPubMedCentral

72.

Santin S, Garcia-Maset R, Ruiz P, Gimenez I, Zamora I, Pena A, Madrid A, Camacho JA, Fraga G, Sanchez-Moreno A, Cobo MA, Bernis C, Ortiz A, de Pablos AL, Pintos G, Justa ML, Hidalgo-Barquero E, Fernandez-Llama P, Ballarin J, Ars E, Torra R, FSGS Spanish Study Group (2009) Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis. Kidney Int 76:1268–1276PubMed

73.

Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, Loirat C, Ozaltin F, Hashmi S, Ulmer F, Cleper R, Ettenger R, Antignac C, Wiggins RC, Zenker M, Hildebrandt F (2008) Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant 23:1291–1297PubMed

74.

Ismaili K, Pawtowski A, Boyer O, Wissing KM, Janssen F, Hall M (2009) Genetic forms of nephrotic syndrome: a single-center experience in Brussels. Pediatr Nephrol 24:287–294PubMed

75.

Lipska BS, Ranchin B, Iatropoulos P, Gellermann J, Melk A, Ozaltin F, Caridi G, Seeman T, Tory K, Jankauskiene A, Zurowska A, Szczepanska M, Wasilewska A, Harambat J, Trautmann A, Peco-Antic A, Borzecka H, Moczulska A, Saeed B, Bogdanovic R, Kalyoncu M, Simkova E, Erdogan O, Vrljicak K, Teixeira A, Azocar M, Schaefer F (2014) Genotype–phenotype associations in WT1 glomerulopathy. Kidney Int 85:1169–1178PubMed

76.

Lipska BS, Iatropoulos P, Maranta R, Caridi G, Ozaltin F, Anarat A, Balat A, Gellermann J, Trautmann A, Erdogan O, Saeed B, Emre S, Bogdanovic R, Azocar M, Balasz-Chmielewska I, Benetti E, Caliskan S, Mir S, Melk A, Ertan P, Baskin E, Jardim H, Davitaia T, Wasilewska A, Drozdz D, Szczepanska M, Jankauskiene A, Higuita LM, Ardissino G, Ozkaya O, Kuzma-Mroczkowska E, Soylemezoglu O, Ranchin B, Medynska A, Tkaczyk M, Peco-Antic A, Akil I, Jarmolinski T, Firszt-Adamczyk A, Dusek J, Simonetti GD, Gok F, Gheissari A, Emma F, Krmar RT, Fischbach M, Printza N, Simkova E, Mele C, Ghiggeri GM, Schaefer F (2013) Genetic screening in adolescents with steroid-resistant nephrotic syndrome. Kidney Int 84:206–213PubMed

77.

Santin S, Ars E, Rossetti S, Salido E, Silva I, Garcia-Maset R, Gimenez I, Ruiz P, Mendizabal S, Luciano Nieto J, Pena A, Camacho JA, Fraga G, Cobo MA, Bernis C, Ortiz A, de Pablos AL, Sanchez-Moreno A, Pintos G, Mirapeix E, Fernandez-Llama P, Ballarin J, Torra R, Group FS, Zamora I, Lopez-Hellin J, Madrid A, Ventura C, Vilalta R, Espinosa L, Garcia C, Melgosa M, Navarro M, Gimenez A, Cots JV, Alexandra S, Caramelo C, Egido J, San Jose MD, de la Cerda F, Sala P, Raspall F, Vila A, Daza AM, Vazquez M, Ecija JL, Espinosa M, Justa ML, Poveda R, Aparicio C, Rosell J, Muley R, Montenegro J, Gonzalez D, Hidalgo E, de Frutos DB, Trillo E, Gracia S, de los Rios FJ (2009) TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis. Nephrol Dial Transplant 24:3089–3096PubMed

78.

Barua M, Brown EJ, Charoonratana VT, Genovese G, Sun H, Pollak MR (2013) Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int 83:316–322PubMed

79.

Heeringa SF, Moller CC, Du J, Yue L, Hinkes B, Chernin G, Vlangos CN, Hoyer PF, Reiser J, Hildebrandt F (2009) A novel TRPC6 mutation that causes childhood FSGS. PLoS One 4:e7771PubMedPubMedCentral

80.

Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, Engelmann S, Vega-Warner V, Fang H, Halbritter J, Somers MJ, Tan W, Shril S, Fessi I, Lifton RP, Bockenhauer D, El-Desoky S, Kari JA, Zenker M, Kemper MJ, Mueller D, Fathy HM, Soliman NA, Hildebrandt F (2015) A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26:1279–1289PubMed

81.

Pollak MR, Alexander MP, Henderson JM (2007) A case of familial kidney disease. Clin J Am Soc Nephrol 2:1367–1374PubMed

82.

Weins A, Kenlan P, Herbert S, Le TC, Villegas I, Kaplan BS, Appel GB, Pollak MR (2005) Mutational and biological analysis of alpha-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol 16:3694–3701PubMed

83.

Brown EJ, Schlondorff JS, Becker DJ, Tsukaguchi H, Tonna SJ, Uscinski AL, Higgs HN, Henderson JM, Pollak MR (2010) Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet 42:72–76PubMed

84.

Boyer O, Nevo F, Plaisier E, Funalot B, Gribouval O, Benoit G, Huynh Cong E, Arrondel C, Tete MJ, Montjean R, Richard L, Karras A, Pouteil-Noble C, Balafrej L, Bonnardeaux A, Canaud G, Charasse C, Dantal J, Deschenes G, Deteix P, Dubourg O, Petiot P, Pouthier D, Leguern E, Guiochon-Mantel A, Broutin I, Gubler MC, Saunier S, Ronco P, Vallat JM, Alonso MA, Antignac C, Mollet G (2011) INF2 mutations in Charcot-Marie-tooth disease with glomerulopathy. N Engl J Med 365:2377–2388PubMed

85.

Tory K, Menyhard DK, Woerner S, Nevo F, Gribouval O, Kerti A, Straner P, Arrondel C, Huynh Cong E, Tulassay T, Mollet G, Perczel A, Antignac C (2014) Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 46:299–304PubMed

86.

Chernin G, Vega-Warner V, Schoeb DS, Heeringa SF, Ovunc B, Saisawat P, Cleper R, Ozaltin F, Hildebrandt F, Members of the GPN Study Group (2010) Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin J Am Soc Nephrol 5:1655–1662PubMedPubMedCentral

87.

Matejas V, Hinkes B, Alkandari F, Al-Gazali L, Annexstad E, Aytac MB, Barrow M, Blahova K, Bockenhauer D, Cheong HI, Maruniak-Chudek I, Cochat P, Dotsch J, Gajjar P, Hennekam RC, Janssen F, Kagan M, Kariminejad A, Kemper MJ, Koenig J, Kogan J, Kroes HY, Kuwertz-Broking E, Lewanda AF, Medeira A, Muscheites J, Niaudet P, Pierson M, Saggar A, Seaver L, Suri M, Tsygin A, Wuhl E, Zurowska A, Uebe S, Hildebrandt F, Antignac C, Zenker M (2010) Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum Mutat 31:992–1002PubMedPubMedCentral

88.

Hasselbacher K, Wiggins RC, Matejas V, Hinkes BG, Mucha B, Hoskins BE, Ozaltin F, Nurnberg G, Becker C, Hangan D, Pohl M, Kuwertz-Broking E, Griebel M, Schumacher V, Royer-Pokora B, Bakkaloglu A, Nurnberg P, Zenker M, Hildebrandt F (2006) Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney Int 70:1008–1012PubMed

89.

Boyer O, Woerner S, Yang F, Oakeley EJ, Linghu B, Gribouval O, Tete MJ, Duca JS, Klickstein L, Damask AJ, Szustakowski JD, Heibel F, Matignon M, Baudouin V, Chantrel F, Champigneulle J, Martin L, Nitschke P, Gubler MC, Johnson KJ, Chibout SD, Antignac C (2013) LMX1B mutations cause hereditary FSGS without extrarenal involvement. J Am Soc Nephrol 24:1216–1222PubMedPubMedCentral

90.

Montini G, Malaventura C, Salviati L (2008) Early coenzyme Q10 supplementation in primary coenzyme Q10 deficiency. N Engl J Med 358:2849–2850PubMed

91.

Buscher AK, Kranz B, Buscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Broking E, Wingen AM, John U, Kemper M, Monnens L, Hoyer PF, Weber S, Konrad M (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:2075–2084PubMedPubMedCentral

92.

Gellermann J, Stefanidis CJ, Mitsioni A, Querfeld U (2010) Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. Pediatr Nephrol 25:1285–1289PubMed

93.

Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F, Arbeitsgemeinschaft Fur Padiatrische Nephrologie Study Group (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732PubMed

94.

Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938PubMedPubMedCentral

95.

Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Oh J, Baskin E, Ksiazek J, Remuzzi G, Erdogan O, Akman S, Dusek J, Davitaia T, Ozkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Ozcakar ZB, Sallay P, Cakar N, Galanti M, Terzic J, Aoun B, Caldas Afonso A, Szymanik-Grzelak H, Lipska BS, Schnaidt S, Schaefer F, PodoNet Consortium (2015) Spectrum of steroid-resistant and congenital nephrotic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600PubMedPubMedCentral

96.

Maas RJ, Deegens JK, van den Brand JA, Cornelissen EA, Wetzels JF (2013) A retrospective study of focal segmental glomerulosclerosis: clinical criteria can identify patients at high risk for recurrent disease after first renal transplantation. BMC Nephrol 14:47PubMedPubMedCentral

97.

Weber S, Tonshoff B (2005) Recurrence of focal-segmental glomerulosclerosis in children after renal transplantation: clinical and genetic aspects. Transplantation 80:S128–S134PubMed

98.

Konigshausen E, Sellin L (2016) Circulating permeability factors in primary focal segmental Glomerulosclerosis: a review of proposed candidates. Biomed Res Int 2016:3765608PubMedPubMedCentral

99.

Wada T, Nangaku M (2015) A circulating permeability factor in focal segmental glomerulosclerosis: the hunt continues. Clin Kidney J 8:708–715PubMedPubMedCentral

100.

Green RC, Lautenbach D, McGuire AL (2015) GINA, genetic discrimination, and genomic medicine. N Engl J Med 372:397–399PubMed

101.

Aswini YB, Varun S (2010) Genetics in public health: rarely explored. Indian J Hum Genet 16:47–54PubMedPubMedCentral

102.

Spoonamore KG, Johnson NM (2016) Who pays? Coverage challenges for cardiovascular genetic testing in U.S. patients. Front Cardiovasc Med 3:14PubMedPubMedCentral

103.

Trosman JR, Weldon CB, Douglas MP, Kurian AW, Kelley RK, Deverka PA, Phillips KA (2017) Payer coverage for hereditary cancer panels: barriers, opportunities, and implications for the precision medicine initiative. J Natl Compr Cancer Netw 15:219–228

104.

Robinson JO, Carroll TM, Feuerman LZ, Perry DL, Hoffman-Andrews L, Walsh RC, Christensen KD, Green RC, McGuire AL (2016) Participants and study Decliners' perspectives about the risks of participating in a clinical trial of whole genome sequencing. J Empir Res Hum Res Ethics 11:21–30PubMedPubMedCentral

105.

Lovric S, Ashraf S, Tan W, Hildebrandt F (2016) Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrol Dial Transplant 31:1802–1813PubMed

106.

Brown EJ, Pollak MR, Barua M (2014) Genetic testing for nephrotic syndrome and FSGS in the era of next-generation sequencing. Kidney Int 85:1030–1038PubMedPubMedCentral

107.

Ha TS (2017) Genetics of hereditary nephrotic syndrome: a clinical review. Korean J Pediatr 60:55–63PubMedPubMedCentral

108.

Sampson MG, Robertson CC, Martini S, Mariani LH, Lemley KV, Gillies CE, Otto EA, Kopp JB, Randolph A, Vega-Warner V, Eichinger F, Nair V, Gipson DS, Cattran DC, Johnstone DB, O'Toole JF, Bagnasco SM, Song PX, Barisoni L, Troost JP, Kretzler M, Sedor JR (2016) Integrative genomics identifies novel associations with APOL1 risk genotypes in black NEPTUNE subjects. J Am Soc Nephrol 27:814–823PubMed

Title: Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?
Authors: Rebecca Preston
Helen M. Stuart
Rachel Lennon
Publication date: 01-02-2019
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 2/2019
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-017-3838-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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