Abstract
The aim of this study is to screen for variants in NPHS1 and NPHS2, in a cohort of Egyptian children with steroid-resistant nephrotic syndrome (SRNS)/focal segmental glomerulosclerosis (FSGS) and compare the prevalence of such variants among other ethnic groups. The study included 25 patients: 21 children diagnosed clinically as steroid-resistant nephrotic syndrome and confirmed as FSGS by renal biopsy and four patients diagnosed as congenital nephrotic syndrome with FSGS. Mutational analysis revealed nine NPHS2 and NPHS1 variants in 13/25 patients with a pathogenic variant detection rate of 52%. NPHS2 variants were found in 8 patients (32%) while five patients from four unrelated families (20%) harbored variants in NPHS1 gene. Six variants were not described before including a likely founder NPHS2 variant in our population, c.596dupA (p.Asn199LysfsTer14). In conclusion, we reported the largest series of patients with SRNS/FSGS from Egypt and identified many novel NPHS1 and NPHS2 variants expanding their mutational spectrum. Further studies on a larger number of patients could provide new insights into the pathogenic mechanisms of SRNS/FSGS which might help in patient’s management and prognosis.
Similar content being viewed by others
Availability of data and material
Not applicable.
Code availability
Not applicable.
References
Abid A, Khaliq S, Shahid S, Lanewala A, Mubarak M, Hashmi S, Kazi J, Masood T, Hafeez F, Naqvi SA, Rizvi SAH, Mehdi SQ (2012) A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan. Gene 502:133–137. https://doi.org/10.1016/j.gene.2012.04.063
Banh TH, Hussain-Shamsy N, Patel V, Vasilevska-Ristovska J, Borges K, Sibbald C, Lipszyc D, Brooke J, Geary D, Langlois V, Reddon M, Pearl R, Levin L, Piekut M, Licht CPB, Radhakrishnan S, Aitken-Menezes K, Harvey E, Hebert D, Piscione TD, Parekh RS (2016) Ethnic differences in incidence and outcomes of childhood nephritic syndrome. Clin J Am Soc Nephrol 11(10):1760–1768. https://doi.org/10.2215/CJN.00380116
Basiratnia M, Yavarian M, Torabinezhad S, Erjaee A (2013) NPHS2 gene in steroid-resistant nephrotic syndrome prevalence, clinical course, and mutational spectrum in south-West Iranian children. Iran J Kidney Dis 7:357–362
Baylarov R, Senol O, Atan M, Berdeli A (2020) NPHS2 gene mutations in azerbaijani children with steroid-resistant nephrotic syndrome. Saudi J Kidney Dis Transpl 31(1):144–149. https://doi.org/10.4103/1319-2442.279934
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 25:1621–1632. https://doi.org/10.1007/s00467-010-1495-0
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(4):937–947. https://doi.org/10.1016/j.kint.2016.10.013
Bouchireb K, Boyer O, Gribouval O, Nevo F, Huynh-Cong E, Morinière V, Campait R, Ars E, Brackman D, Dantal J, Eckart P, Gigante M et al (2014) NPHS2 mutations in steroid-resistant nephrotic syndrome: a mutation update and the associated phenotypic spectrum. Hum Mutat 35:178–186. https://doi.org/10.1002/humu.22485
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(4):349–354. https://doi.org/10.1038/74166
Bullich G, Trujillano D, Santin S, Ossowski S, Mendizábal S, Fraga G, Madrid A, Ariceta G, Ballarín J, Torra R, Estivill X, Ars E (2015) Targeted next generation sequencing in steroid-resistant nephritic syndrome: mutations in multiple glomerular genes may influence disease severity. Eur J Hum Genet 23(9):1192–1199. https://doi.org/10.1038/ejhg.2014.252
Büscher AK, Kranz B, Büscher R, Hildebrandt F, Dworniczak B, Pennekamp P, Kuwertz-Bröking 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(11):2075–2084. https://doi.org/10.2215/CJN.01190210
Caridi G, Bertelli R, Carrea A, Di Duca M, Catarsi P, Artero M, Carraro M, Zennaro C, Candiano G, Musante L, Seri M, Ginevri F, Perfumo F, Ghiggeri GM (2001) Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J Am Soc Nephrol 12:2742–2746. https://doi.org/10.1681/ASN.V12122742
Cheong HI (2020) Genetic tests in children with steroid-resistant nephrotic syndrome. Kidney Res Clin Pract 39(1):7–16. https://doi.org/10.23876/j.krcp.20.001
Chernin G, Heeringa SF, Gbadegesin R, Liu J, Hinkes BG, Vlangos CN, Vega-Warner V, Hildebrandt F (2008) Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:1455–1460. https://doi.org/10.1007/s00467-008-0861-7
Cho HY, Lee JH, Choi HJ, Lee BH, Ha IS, Choi Y, Cheong HI (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:63–70. https://doi.org/10.1007/s00467-007-0620-1
Dossier C, Lapidus N, Bayer F, Sellier-Leclerc AL, Boyer O, de Pontual L, May A, Nathanson S, Orzechowski C, Simon T, Carrat F, Deschenes G (2016) Epidemiology of idiopathic nephrotic syndrome in children: endemic or epidemic? Pediat Nephrol 31(12):2299–2308. https://doi.org/10.1007/s00467-016-3509-z
El Bakkali L, Pereira R, Kuik DJ, Ket JC, vanWijk JA (2011) Nephrotic syndrome in the Netherlands: a populationbased cohort study and a review of the literature. Pediat Nephrol 26(8):1241–1246. https://doi.org/10.1007/s00467-011-1851-8
Ha TS (2017) Genetics of hereditary nephrotic syndrome: a clinical review. Korean J Pediatr 60(3):55–63. https://doi.org/10.3345/kjp.2017.60.3.55
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 366:1508–1514. https://doi.org/10.1056/NEJMoa1110813
Hinkes BG, Mucha B, Vlangos CN, Gbadegesin R, Liu J, Hasselbacher K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F; Arbeitsgemeinschaft für 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(4):e907-919. https://doi.org/10.1542/peds.2006-2164
Jaffer A, Unnisa W, Raju D, Jahan P (2014) NPHS2 mutation analysis and primary nephrotic syndrome in south Indians. Nephrology 19:398–403. https://doi.org/10.1111/nep.12241
Joshi S, Andersen R, Jespersen B, Rittig S (2013) Genetics of steroid-resistant nephrotic syndrome: a review of mutation spectrum and suggested approach for genetic testing. Acta Paediatr 102(9):844–856. https://doi.org/10.1111/apa.12317
Jungraithmayr TC, Hofer K, Cochat P, Chernin G, Cortina G, Fargue S, Grimm P, Knueppel T, Kowarsch A, Neuhaus T, Pagel P, Pfeiffer KP, Schäfer F, Schönermarck U, Seeman T, Toenshoff B, Weber S, WinnMP ZJ, Zimmerhackl LB (2011) Screening for NPHS2 mutations may help predict FSGS recurrence after transplantation. J Am Soc Nephrol 22:579–585. https://doi.org/10.1681/ASN.2010010029
Kari JA, El-Desoky SM, Gari M, Malik K, Vega-Warner V, Lovric S, Bockenhauer D (2013) Steroid-resistant nephrotic syndrome: impact of genetic testing. Ann Saudi Med 33(6):533–538. https://doi.org/10.5144/0256-4947.2013.533
Lahdenkari AT, Suvanto M, Kajantie E, Koskimies O, Kestilä M, Jalanko H (2005) Clinical features and outcome of childhood minimal change nephrotic syndrome: Is genetics involved? Pediatr Nephrol 20:1073–1080. https://doi.org/10.1007/s00467-005-1965-y
Lenkkeri U, Männikkö M, McCready P, Lamerdin J, Gribouval O, Niaudet PM, Antignac CK, Kashtan CE, Homberg C, Olsen A, Kestilä M, Tryggvason K (1999) Structure of the gene for congenital nephrotic syndrome of the finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64(1):51–61. https://doi.org/10.1086/302182
Lepori N, Zand L, Sethi S, Fernandez-Juarez G, Fervenza FC (2018) Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults. Clin Kidney J 11(2):179–190. https://doi.org/10.1093/ckj/sfx143
Liu L, Doné SC, Khoshnoodi J, Bertorello A, Wartiovaara J, Berggren PO, Tryggvason K (2001) Defective nephrin trafficking caused by missense mutations in the NPHS1 gene: insight into the mechanisms of congenital nephrotic syndrome. Hum Mol Genet 10(23):2637–2644. https://doi.org/10.1093/hmg/10.23.2637
Lombel RM, Gipson DS, Hodson EM (2013) Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediat Nephrol 28(3):415–426. https://doi.org/10.1007/s00467-012-2310-x
Machuca E, Benoit G, Nevo F, Tête MJ, Gribouval O, Pawtowski A, Brandström P, Loirat C, Niaudet P, Gubler MC, Antignac C (2010) Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol 21(7):1209–1217. https://doi.org/10.1681/ASN.2009121309
Mbarek IB, Abroug S, Omezzine A, Pawtowski A, Gubler MC, Bouslama A, Harbi A, Antignac C (2011) Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children. Pediatr Nephrol 26:241–249. https://doi.org/10.1007/s00467-010-1694-8
Mekahli D, Liutkus A, Ranchin B, Yu A, Bessenay L, Girardin E, Damme-Lombaerts RV, Palcoux J-B, Cachat F, Lavocat M-P, Bourdat-Michel G, Nobili F, Cochat P (2009) Long-term outcome of idiopathic steroid-resistant nephrotic syndrome: a multicenter study. Pediatr Nephrol 24(8):1525–1532. https://doi.org/10.1007/s00467-009-1138-5
Nagano C, Yamamura T, Horinouchi T, Aoto Y, Ishiko S, Sakakibara N, Shima Y, Nakanishi K, Nagase H, Iijima K, Nozu K (2020) Comprehensive genetic diagnosis of Japanese patients with severe proteinuria. Sci Rep 10:270. https://doi.org/10.1038/s41598-019-57149-5
Niaudet P (2004) Steroid sensitive idiopatic syndrome in children. In: Avner ED, Harmon WE (eds) Pediatric nephrology, 5th edn. Lippinccott Wiliams-Wilkins, Philadelphia, p 543
Noone DG, Iijima K, Parekh R (2018) Idiopathic nephrotic syndrome in children. Lancet 392(10141):61–74. https://doi.org/10.1016/S0140-6736(18)30536-1
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 19:1871–1878. https://doi.org/10.1681/ASN.2008010059
Renda R, Aydoğ Ö, Bülbül M, Çakıcı EK (2016) Children with steroid-resistant nephrotic syndrome: a single-center study. Int J Pediatr 4:1233–1242
Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf E-M, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrandt F, Arbeitsgemeinschaft Für Pädiatrische Nephrologie Study Group (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732. https://doi.org/10.1097/01.asn.0000113552.59155.72
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(6):1279–1289. https://doi.org/10.1681/ASN.2014050489
Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S et al (2005) Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney Int 67:1248–1255. https://doi.org/10.1111/j.1523-1755.2005.00202.x
Sampson MG (2017) The democratization of genomic inquiry empowers our understanding of nephrotic syndrome. Transplantation 101(12):2814–2815. https://doi.org/10.1097/TP.0000000000001897
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 (2009) Nephrin mutations cause childhood- and adult onset focal segmental glomerulosclerosis. Kidney Int 76:1268–1276. https://doi.org/10.1038/ki.2009.381
Santin S, Tazon-Vega B, Silva I, Cobo MA, Gimenez I, Ruiz P, García-Maset R, Ballarín J, Torra R, Ars E; FSGS Spanish Study Group (2011) Clinical value of NPHS2 analysis in early- and adult-onset steroid-resistant nephritic syndrome. Clin J Am Soc Nephrol 6:344–354. https://doi.org/10.2215/CJN.03770410
Serajpour N, Karimi B, Khosravi P, Hooman N, Hosseini R, Shojaei A (2019) Molecular genetic analysis of steroid resistant nephrotic syndrome, detection of a novel mutation. Iran J Kidney Dis 13:165–172
Tasic V, Gucev Z, Polenakovic M (2015) Steroid resistant nephrotic syndrome-genetic consideration. Pril (makedon Akad Nauk Umet Odd Med Nauki) 36(3):5–12. https://doi.org/10.1515/prilozi-2015-0073
Thomas MM, Abdel-Hamid MS, Mahfouz NN, Ghobrial EE (2017) Genetic mutation in Egyptian children with steroid-resistant nephrotic syndrome. J Formos Med Assoc 117:48–53. https://doi.org/10.1016/j.jfma.2017.02.012
Trautmann A, Bodria M, Ozaltin F, Gheisari A, Melk A, Azocar M, Anarat A, Caliskan S, Emma F, Gellermann J, Papachristou F, Firszt-Adamczyk A, Urasinski T, Testa S, Krmar RT, Hyla-Klekot L, Pasini A, et al., PodoNet Consortium (2015) Spectrum of steroid-resistant and congenital nephritic syndrome in children: the PodoNet registry cohort. Clin J Am Soc Nephrol 10:592–600. https://doi.org/10.2215/CJN.06260614.
Trautmann A, Schnaidt S, Lipska-Zietkiewicz 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 et al (2017) Long-term outcome of steroid-resistant nephrotic syndrome in children. J Am Soc Nephrol 28(10):3055–3065. https://doi.org/10.1681/ASN.2016101121
Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease associated allele. J Clin Invest 110:1659–1666. https://doi.org/10.1172/JCI16242
Tullus K, Webb H, Bagga A (2018) Management of steroid resistant nephrotic syndrome in children and adolescents. Lancet Child Adolesc Health 2(12):880–890. https://doi.org/10.1016/S2352-4642(18)30283-9
Vasudevan A, Siji A, Raghavendra A, Sridhar TS, Phadke KD (2012) NPHS2 mutations in Indian children with sporadic early steroid resistant nephrotic syndrome. Indian Pediatr 49:231–233. https://doi.org/10.1007/s13312-012-0057-x
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 32:1181–1192. https://doi.org/10.1007/s00467-017-3590-y
Warejko JK, Tan W, Daga A, Schapiro D, Lawson JA, Shril S, Lovric S, Ashraf S, Rao J, Hermle T et al (2018) Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 13:53–62. https://doi.org/10.2215/CJN.04120417
Yu Z, Ding J, Huang J, Yao Y, Xiao H, Zhang J, Liu J, Yang J (2005) Mutations in NPHS2 in sporadic steroid resistant nephritic syndrome in Chinese children. Nephrol Dial Transplant 20:902–908. https://doi.org/10.1093/ndt/gfh769
Funding
No funding was received for conducting this study.
Author information
Authors and Affiliations
Contributions
All authors contributed to the study’s conception and design. Material preparation, data collection and analysis were performed by MMT, HMA, OEB, SHED and AR. Methodology was performed by MSAH. The first draft of the manuscript was written by MMT. Writing—review and editing: MMT, HMA and MSAH. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors have no conflicts of interest to declare that are relevant to the content of this article.
Ethics approval
This study was approved by the ethical scientific of the National Research Centre (NRC), Cairo, Egypt and was conducted in accordance with the NRC bylaws for human research. It conforms to the provisions of the Declaration of Helsinki in 2000.
Consent to participate
An informed consent to participate in the study was obtained from all the patients or their parents.
Consent for publication
Patients or their legal guardians have signed informed consent regarding publishing their data.
Additional information
Communicated by Shuhua Xu.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Thomas, M.M., Ahmed, H.M., El-Dessouky, S.H. et al. Spectrum of NPHS1 and NPHS2 variants in egyptian children with focal segmental glomerular sclerosis: identification of six novel variants and founder effect. Mol Genet Genomics 297, 689–698 (2022). https://doi.org/10.1007/s00438-022-01877-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00438-022-01877-3