Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome.
United States
chronic kidney disease
chronic renal insufficiency
genetic testing
humans
medical genetics
multiple drug resistance
nephrotic syndrome
phenotype
retrospective studies
steroids
whole exome sequencing
whole-exome sequencing
workflow
Journal
Clinical journal of the American Society of Nephrology : CJASN
ISSN: 1555-905X
Titre abrégé: Clin J Am Soc Nephrol
Pays: United States
ID NLM: 101271570
Informations de publication
Date de publication:
07 01 2020
07 01 2020
Historique:
received:
17
05
2019
accepted:
08
10
2019
pubmed:
14
12
2019
medline:
1
6
2021
entrez:
14
12
2019
Statut:
ppublish
Résumé
Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients. All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies. Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.
Sections du résumé
BACKGROUND AND OBJECTIVES
Nephrotic syndrome is a typical presentation of genetic podocytopathies but occasionally other genetic nephropathies can present as clinically indistinguishable phenocopies. We hypothesized that extended genetic testing followed by reverse phenotyping would increase the diagnostic rate for these patients.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
All patients diagnosed with nephrotic syndrome and referred to our center between 2000 and 2018 were assessed in this retrospective study. When indicated, whole-exome sequencing and
RESULTS
A total of 111 patients (64 steroid-resistant and 47 steroid-sensitive) were included in the study. Not a single pathogenic variant was detected in the steroid-sensitive group. Overall, 30% (19 out of 64) of steroid-resistant patients had pathogenic variants in podocytopathy genes, whereas a substantial number of variants were identified in other genes, not commonly associated with isolated nephrotic syndrome. Reverse phenotyping, on the basis of a personalized diagnostic workflow, permitted to identify previously unrecognized clinical signs of an unexpected underlying genetic nephropathy in a further 28% (18 out of 64) of patients. These patients showed similar multidrug resistance, but different long-term outcome, when compared with genetic podocytopathies.
CONCLUSIONS
Reverse phenotyping increased the diagnostic accuracy in patients referred with the diagnosis of steroid-resistant nephrotic syndrome.
Identifiants
pubmed: 31831576
pii: 01277230-202001000-00014
doi: 10.2215/CJN.06060519
pmc: PMC6946071
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
89-100Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 by the American Society of Nephrology.
Références
Kidney Disease Improving global outcomes (KDIGO) Glomerulonephritis Work Group: KDIGO clinical practice guidelines for glomerulonephritis. Kidney Int Suppl (2011) 2: 139–274, 2012
Noone DG, Iijima K, Parekh R: Idiopathic nephrotic syndrome in children. Lancet 392: 61–74, 2018 29910038
Gipson DS, Chin H, Presler TP, Jennette C, Ferris ME, Massengill S, Gibson K, Thomas DB: Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol 21: 344–349, 2006 16395603
Samuel SM, Flynn R, Zappitelli M, Dart A, Parekh R, Pinsk M, Mammen C, Wade A, Scott SD; Canadian Childhood Nephrotic Syndrome Project Team*: Factors influencing practice variation in the management of nephrotic syndrome: A qualitative study of pediatric nephrology care providers. CMAJ Open 5: E424–E430, 2017 28592406
Büscher AK, Beck BB, Melk A, Hoefele J, Kranz B, Bamborschke D, Baig S, Lange-Sperandio B, Jungraithmayr T, Weber LT, Kemper MJ, Tönshoff B, Hoyer PF, Konrad M, Weber S; German Pediatric Nephrology Association (GPN): Rapid response to cyclosporin a and favorable renal outcome in nongenetic versus genetic steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 11: 245–253, 2016 26668027
Trautmann A, Schnaidt S, Lipska-Ziętkiewicz BS, Bodria M, Ozaltin F, Emma F, Anarat A, Melk A, Azocar M, Oh J, Saeed B, Gheisari A, Caliskan S, Gellermann J, Higuita LMS, Jankauskiene A, Drozdz D, Mir S, Balat A, Szczepanska M, Paripovic D, Zurowska A, Bogdanovic R, Yilmaz A, Ranchin B, Baskin E, Erdogan O, Remuzzi G, Firszt-Adamczyk A, Kuzma-Mroczkowska E, Litwin M, Murer L, Tkaczyk M, Jardim H, Wasilewska A, Printza N, Fidan K, Simkova E, Borzecka H, Staude H, Hees K, Schaefer F; PodoNet Consortium: Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol 28: 3055–3065, 2017 28566477
Romagnani P, Remuzzi G, Glassock R, Levin A, Jager KJ, Tonelli M, Massy Z, Wanner C, Anders HJ: Chronic kidney disease. Nat Rev Dis Primers 3: 17088, 2017 29168475
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: Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol 26: 230–236, 2015 25060053
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; SRNS Study Group: A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol 26: 1279–1289, 2015 25349199
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: Spectrum of mutations in Chinese children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 32: 1181–1192, 2017 28204945
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: Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney Int 91: 937–947, 2017 28117080
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, Özkaya O, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, Özcakar 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: Spectrum of steroid-resistant and congenital nephrotic syndrome in children: The PodoNet registry cohort. Clin J Am Soc Nephrol 10: 592–600, 2015 25635037
Ashraf S, Kudo H, Rao J, Kikuchi A, Widmeier E, Lawson JA, Tan W, Hermle T, Warejko JK, Shril S, Airik M, Jobst-Schwan T, Lovric S, Braun DA, Gee HY, Schapiro D, Majmundar AJ, Sadowski CE, Pabst WL, Daga A, van der Ven AT, Schmidt JM, Low BC, Gupta AB, Tripathi BK, Wong J, Campbell K, Metcalfe K, Schanze D, Niihori T, Kaito H, Nozu K, Tsukaguchi H, Tanaka R, Hamahira K, Kobayashi Y, Takizawa T, Funayama R, Nakayama K, Aoki Y, Kumagai N, Iijima K, Fehrenbach H, Kari JA, El Desoky S, Jalalah S, Bogdanovic R, Stajić N, Zappel H, Rakhmetova A, Wassmer SR, Jungraithmayr T, Strehlau J, Kumar AS, Bagga A, Soliman NA, Mane SM, Kaufman L, Lowy DR, Jairajpuri MA, Lifton RP, Pei Y, Zenker M, Kure S, Hildebrandt F: Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun 9: 1960, 2018 29773874
Gast C, Pengelly RJ, Lyon M, Bunyan DJ, Seaby EG, Graham N, Venkat-Raman G, Ennis S: Collagen (COL4A) mutations are the most frequent mutations underlying adult focal segmental glomerulosclerosis. Nephrol Dial Transplant 31: 961–970, 2016 26346198
Pierides A, Voskarides K, Athanasiou Y, Ioannou K, Damianou L, Arsali M, Zavros M, Pierides M, Vargemezis V, Patsias C, Zouvani I, Elia A, Kyriacou K, Deltas C: Clinico-pathological correlations in 127 patients in 11 large pedigrees, segregating one of three heterozygous mutations in the COL4A3/ COL4A4 genes associated with familial haematuria and significant late progression to proteinuria and chronic kidney disease from focal segmental glomerulosclerosis. Nephrol Dial Transplant 24: 2721–2729, 2009 19357112
Fogo AB: The spectrum of FSGS: Does pathology matter? Nephrol Dial Transplant 25: 1034–1036, 2010 20083475
Saida K, Kamijo Y, Matsuoka D, Noda S, Hidaka Y, Mori T, Shimojo H, Ehara T, Miura K, Takita J, Sekine T, Igarashi T, Koike K: A case of adult Dent disease in Japan with advanced chronic kidney disease. CEN Case Rep 3: 132–138, 2014 28509186
Fervenza FC: A patient with nephrotic-range proteinuria and focal global glomerulosclerosis. Clin J Am Soc Nephrol 8: 1979–1987, 2013 23886564
Malone AF, Phelan PJ, Hall G, Cetincelik U, Homstad A, Alonso AS, Jiang R, Lindsey TB, Wu G, Sparks MA, Smith SR, Webb NJ, Kalra PA, Adeyemo AA, Shaw AS, Conlon PJ, Jennette JC, Howell DN, Winn MP, Gbadegesin RA: Rare hereditary COL4A3/COL4A4 variants may be mistaken for familial focal segmental glomerulosclerosis. Kidney Int 86: 1253–1259, 2014 25229338
Vallés P, Peralta M, Carrizo L, Martin L, Principi I, Gonzalez A, Manucha W: Follow-up of steroid-resistant nephrotic syndrome: Tubular proteinuria and enzymuria. Pediatr Nephrol 15: 252–258, 2000 11149121
He G, Zhang H, Cao S, Xiao H, Yao Y: Dent’s disease complicated by nephrotic syndrome: A case report. Intractable Rare Dis Res 5: 297–300, 2016 27904828
Wang X, Anglani F, Beara-Lasic L, Mehta AJ, Vaughan LE, Herrera Hernandez L, Cogal A, Scheinman SJ, Ariceta G, Isom R, Copelovitch L, Enders FT, Del Prete D, Vezzoli G, Paglialonga F, Harris PC, Lieske JC; Investigators of the Rare Kidney Stone Consortium: Glomerular pathology in dent disease and its association with kidney function. Clin J Am Soc Nephrol 11: 2168–2176, 2016 27697782
Koulousios K, Stylianou K, Pateinakis P, Zamanakou M, Loules G, Manou E, Kyriklidou P, Katsinas C, Ouzouni A, Kyriazis J, Speletas M, Germenis AE: Fabry disease due to D313Y and novel GLA mutations. BMJ Open 7: e017098, 2017 28988177
du Moulin M, Koehn AF, Golsari A, Dulz S, Atiskova Y, Patten M, Münch J, Avanesov M, Ullrich K, Muschol N: The mutation p.D313Y is associated with organ manifestation in Fabry disease. Clin Genet 92: 528–533, 2017 28276057
Köping M, Shehata-Dieler W, Cebulla M, Rak K, Oder D, Müntze J, Nordbeck P, Wanner C, Hagen R, Schraven S: Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease. PLoS One 12: e0188103, 2017 29161295
National Cancer Institute. Available at: https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/phenocopy . Accessed July 15, 2019
Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S, Lovric S, Ashraf S, Rao J, Hermle T, Jobst-Schwan T, Widmeier E, Majmundar AJ, Schneider R, Gee HY, Schmidt JM, Vivante A, van der Ven AT, Ityel H, Chen J, Sadowski CE, Kohl S, Pabst WL, Nakayama M, Somers MJG, Rodig NM, Daouk G, Baum M, Stein DR, Ferguson MA, Traum AZ, Soliman NA, Kari JA, El Desoky S, Fathy H, Zenker M, Bakkaloglu SA, Müller D, Noyan A, Ozaltin F, Cadnapaphornchai MA, Hashmi S, Hopcian J, Kopp JB, Benador N, Bockenhauer D, Bogdanovic R, Stajić N, Chernin G, Ettenger R, Fehrenbach H, Kemper M, Munarriz RL, Podracka L, Büscher R, Serdaroglu E, Tasic V, Mane S, Lifton RP, Braun DA, Hildebrandt F: Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 13: 53–62, 2018 29127259
Zhang H, Wang F, Xiao H, Yao Y: The ratio of urinary α1-microglobulin to microalbumin can be used as a diagnostic criterion for tubuloproteinuria. Intractable Rare Dis Res 7: 46–50, 2018 29552446
Li H, Durbin R: Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25: 1754–1760, 2009 19451168
Thorvaldsdóttir H, Robinson JT, Mesirov JP: Integrative Genomics Viewer (IGV): High-performance genomics data visualization and exploration. Brief Bioinform 14: 178–192, 2013 22517427
McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, Garimella K, Altshuler D, Gabriel S, Daly M, DePristo MA: The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20: 1297–1303, 2010 20644199
Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R; 1000 Genome Project Data Processing Subgroup: The Sequence Alignment/Map format and SAMtools. Bioinformatics 25: 2078–2079, 2009 19505943
Wang K, Li M, Hakonarson H: ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38: e164, 2010 20601685
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee: Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17: 405–424, 2015 25741868
Tory K, Menyhárd DK, Woerner S, Nevo F, Gribouval O, Kerti A, Stráner P, Arrondel C, Huynh Cong E, Tulassay T, Mollet G, Perczel A, Antignac C: Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nat Genet 46: 299–304, 2014 24509478
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: Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329: 841–845, 2010 20647424
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, Büscher 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: FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun 7: 10822, 2016 26905694
Fine RN: Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children. Pediatr Nephrol 22: 496–502, 2007 17186280
Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Li Y, Zhang J, Nestor J, Krithivasan P, Lam WY, Mitrotti A, Piva S, Kil BH, Chatterjee D, Reingold R, Bradbury D, DiVecchia M, Snyder H, Mu X, Mehl K, Balderes O, Fasel DA, Weng C, Radhakrishnan J, Canetta P, Appel GB, Bomback AS, Ahn W, Uy NS, Alam S, Cohen DJ, Crew RJ, Dube GK, Rao MK, Kamalakaran S, Copeland B, Ren Z, Bridgers J, Malone CD, Mebane CM, Dagaonkar N, Fellström BC, Haefliger C, Mohan S, Sanna-Cherchi S, Kiryluk K, Fleckner J, March R, Platt A, Goldstein DB, Gharavi AG: Diagnostic utility of exome sequencing for kidney disease. N Engl J Med 380: 142–151, 2019 30586318
Bullich G, Domingo-Gallego A, Vargas I, Ruiz P, Lorente-Grandoso L, Furlano M, Fraga G, Madrid Á, Ariceta G, Borregán M, Piñero-Fernández JA, Rodríguez-Peña L, Ballesta-Martínez MJ, Llano-Rivas I, Meñica MA, Ballarín J, Torrents D, Torra R, Ars E: A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases. Kidney Int 94: 363–371, 2018 29801666
Yao T, Udwan K, John R, Rana A, Haghighi A, Xu L, Hack S, Reich HN, Hladunewich MA, Cattran DC, Paterson AD, Pei Y, Barua M: Integration of genetic testing and pathology for the diagnosis of adults with FSGS [published online ahead of print January 15, 2019]. Clin J Am Soc Nephrol 10.2215/CJN.08750718 30647093
doi: 10.2215/CJN.08750718
D’Agati VD, Kaskel FJ, Falk RJ: Focal segmental glomerulosclerosis. N Engl J Med 365: 2398–2411, 2011 22187987
Gallon L, Leventhal J, Skaro A, Kanwar Y, Alvarado A: Resolution of recurrent focal segmental glomerulosclerosis after retransplantation. N Engl J Med 366: 1648–1649, 2012 22533598
Francis A, Trnka P, McTaggart SJ: Long-term outcome of kidney transplantation in recipients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 11: 2041–2046, 2016 27797890