CENTRAL ASIAN JOURNAL OF NEPHROLOGY
Case Report
Jun 05, 2026 7 2

Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report

Mohammad Elraggal 1 2 * ,
Rowan Zyada 1 * ,
Rasha Gawish 3
1 Nephrology Department, Kidney and Urology Center, Alexandria, Egypt2 Nephrology Department, Johns Hopkins Aramco Healthcare (JHAH), Dhahran, Saudi Arabia3 Nephrology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt* Corresponding Author
Central Asian Journal of Nephrology, 2(2), 2026, cajn016, https://doi.org/10.63946/cajn/18719
Publication date: Jun 05, 2026
Full Text (PDF)

ABSTRACT

Focal segmental glomerulosclerosis (FSGS) is a common pathological lesion in kidney biopsies with diverse etiologies, including genetic mutations.
We report a case of a 39-year-old man presenting with proteinuria of 2 g/day, normal kidney function, and no nephrotic syndrome. A kidney biopsy revealed findings consistent with FSGS (not otherwise specified )NOS( type), and whole-exome sequencing (WES) identified two heterozygous variants in the CRB2 gene: c.3219C>G (likely pathogenic) and c.1864G>A (variant of uncertain significance). The patient was managed conservatively with renin-angiotensin-aldosterone system (RAAS) inhibitor and Sodium-Glucose cotransporter 2 (SGLT2) inhibitor, resulting in sustained proteinuria reduction and preservation of kidney function over a three-year follow-up. This report highlights a possible novel presentation of CRB2 mutation-associated FSGS without steroid resistance or nephrotic syndrome, that was successfully managed without immunosuppression.

KEYWORDS

FSGS Glomerulonephritis Genetics

CITATION (Vancouver)

Elraggal M, Zyada R, Gawish R. Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report. Central Asian Journal of Nephrology. 2026;2(2):cajn016. https://doi.org/10.63946/cajn/18719
APA
Elraggal, M., Zyada, R., & Gawish, R. (2026). Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report. Central Asian Journal of Nephrology, 2(2), cajn016. https://doi.org/10.63946/cajn/18719
Harvard
Elraggal, M., Zyada, R., and Gawish, R. (2026). Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report. Central Asian Journal of Nephrology, 2(2), cajn016. https://doi.org/10.63946/cajn/18719
AMA
Elraggal M, Zyada R, Gawish R. Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report. Central Asian Journal of Nephrology. 2026;2(2), cajn016. https://doi.org/10.63946/cajn/18719
Chicago
Elraggal, Mohammad, Rowan Zyada, and Rasha Gawish. "Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report". Central Asian Journal of Nephrology 2026 2 no. 2 (2026): cajn016. https://doi.org/10.63946/cajn/18719
MLA
Elraggal, Mohammad et al. "Adult-Onset Focal Segmental Glomerulosclerosis Associated with CRB2 Gene Variants, a Case Report". Central Asian Journal of Nephrology, vol. 2, no. 2, 2026, cajn016. https://doi.org/10.63946/cajn/18719

REFERENCES

  1. De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating primary, genetic, and secondary FSGS in adults: A clinicopathologic approach. J Am Soc Nephrol. 2018;29(3):759–774. doi:10.1681/ASN.2017090958
  2. Miao J, Pinto E Vairo F, Hogan MC, Erickson SB, El Ters M, Bentall AJ, et al. Identification of genetic causes of focal segmental glomerulosclerosis increases with proper patient selection. Mayo Clin Proc. 2021;96(9):2342–2353. doi:10.1016/j.mayocp.2021.01.027
  3. De Vriese AS, Wetzels JF, Glassock RJ, Sethi S, Fervenza FC. Therapeutic trials in adult FSGS: lessons learned and the road forward. Nat Rev Nephrol. 2021;17(9):619–630. doi:10.1038/s41581-021-00427-1
  4. Yao T, Udwan K, John R, Rana A, Haghighi A, Xu L, et al. Integration of genetic testing and pathology for the diagnosis of adults with FSGS. Clin J Am Soc Nephrol. 2019;14(2):213–223. doi:10.2215/CJN.08750718
  5. D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis. 2004;43(2):368–382. doi:10.1053/j.ajkd.2003.10.024
  6. Ebarasi L, Ashraf S, Bierzynska A, Gee HY, McCarthy HJ, Lovric S, et al. Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet. 2015;96(1):153–161. doi:10.1016/j.ajhg.2014.11.014
  7. Malakasioti G, Iancu D, Milovanova A, Tsygin A, Horinouchi T, Nagano C, et al. A multicenter retrospective study of calcineurin inhibitors in nephrotic syndrome secondary to podocyte gene variants. Kidney Int. 2023;103(5):962–972. doi:10.1016/j.kint.2023.01.032
  8. Elrggal M, Zyada R. Immunoglobulin A nephropathy prevalence in Egypt: a narrative overview of glomerulonephritis spectrum (1995–2023). 2024;24(4):196–197. doi:10.4103/jpgm.jpgm_123_24
  9. Lepori N, Zand L, Sethi S, Fernandez-Juarez G, Fervenza FC. Clinical and pathological phenotype of genetic causes of focal segmental glomerulosclerosis in adults. Clin Kidney J. 2018;11(2):179–190. doi:10.1093/ckj/sfx143
  10. Slavotinek A, Kaylor J, Pierce H, Cahr M, Deward SJ, Schneidman-Duhovny D, et al. CRB2 mutations produce a phenotype resembling congenital nephrosis, Finnish type, with cerebral ventriculomegaly and raised alpha-fetoprotein. Am J Hum Genet. 2015;96:162–169. doi:10.1016/j.ajhg.2014.11.013
  11. Lu J, Guo YN, Dong LQ. Crumbs homolog 2 mutation in two siblings with steroid-resistant nephrotic syndrome: Two case reports. World J Clin Cases. 2021;9(13):3056–3062. doi:10.12998/wjcc.v9.i13.3056
  12. Rood IM, Deegens JKJ, Wetzels JFM. Genetic causes of focal segmental glomerulosclerosis: implications for clinical practice. Nephrol Dial Transplant. 2012;27(3):882–890. doi:10.1093/ndt/gfr771
  13. Reiser J, Polu KR, Möller CC, Kenlan P, Altintas MM, Wei C, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37(7):739–744. doi:10.1038/ng1592
  14. Weins A, Kenlan P, Herbert S. Mutational and biological analysis of α-actinin-4 in focal segmental glomerulosclerosis. J Am Soc Nephrol. 2005;16(12):3694–3701. doi:10.1681/ASN.2005040368
  15. Brown EJ, Schlondorff JS, Becker DJ. Mutations in the formin gene INF2 cause focal segmental glomerulosclerosis. Nat Genet. 2010;42(1):72–76. doi:10.1038/ng.505
  16. Thompson BJ, Pichaud F, Röper K. Sticking together the Crumbs - an unexpected function for an old friend. Nat Rev Mol Cell Biol. 2013;14(5):307–314. doi:10.1038/nrm3555
  17. Santín S, Bullich G, Tazón-Vega B, García-Maset R, Giménez I, Silva I, et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol. 2011;6(5):1139–1148. doi:10.2215/CJN.05260610
  18. Sadowski CE, Lovric S, Ashraf S, Pabst WL, Gee HY, Kohl S, et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J Am Soc Nephrol. 2015;26(6):1279–1289. doi:10.1681/ASN.2014050489
  19. Barua M, Brown EJ, Charoonratana VT, Genovese G, Sun H, Pollak MR. Mutations in the INF2 gene account for a significant proportion of familial but not sporadic focal and segmental glomerulosclerosis. Kidney Int. 2013;83(2):316–322. doi:10.1038/ki.2012.356
  20. Boyer O, Benoit G, Gribouval O. Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. J Am Soc Nephrol. 2011;22(2):239–245. doi:10.1681/ASN.2010050518
  21. Büscher AK, Konrad M, Nagel M. Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients. Clin Nephrol. 2012;78(1):47–53. doi:10.5414/CN107192
  22. Zhang Q, Ma J, Xie J, Wang Z, Zhu B, Hao X, et al. Screening of ACTN4 and TRPC6 mutations in a Chinese cohort of patients with adult-onset familial focal segmental glomerulosclerosis. Contrib Nephrol. 2013;181:91–100. doi:10.1159/000348465
  23. Santín S, Ars E, Rossetti S, Salido E, Silva I, García-Maset R, et al. TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2009;24(10):3089–3096. doi:10.1093/ndt/gfp258
  24. Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, et al. NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J Clin Invest. 2002;110(11):1659–1666. doi:10.1172/JCI16242
  25. Clinical and epidemiological assessment of steroid-resistant nephrotic syndrome associated with the NPHS2 R229Q variant. Kidney Int. 2009;75(7):727–735. doi:10.1038/ki.2008.650
  26. Tonna SJ, Needham A, Polu K, Uscinski A, Appel GB, Falk RJ, et al. NPHS2 variation in focal and segmental glomerulosclerosis. BMC Nephrol. 2008;9(1):13. doi:10.1186/1471-2369-9-13
  27. Knust E, Dietrich U, Tepass U, Bremer KA, Weigel D, Vässin H, et al. EGF homologous sequences encoded in the genome of Drosophila melanogaster, and their relation to neurogenic genes. EMBO J. 1987;6(3):761–766. doi:10.1002/j.1460-2075.1987.tb04812.x
  28. Katoh M, Katoh M. Identification and characterization of Crumbs homolog 2 gene at human chromosome 9q33.3. Int J Oncol. 2004;24(3):743–749. doi:10.3892/ijo.24.3.743
  29. Key role for CRB2 in the maintenance of apicobasal polarity in retinal pigment epithelial cells. Front Cell Dev Biol. 9. doi:10.3389/fcell.2021.1234567
  30. Ebarasi L, He L, Hultenby K, Takemoto M, Betsholtz C, Tryggvason K, et al. A reverse genetic screen in the zebrafish identifies crb2b as a regulator of the glomerular filtration barrier. Dev Biol. 2009;334(1):1–9. doi:10.1016/j.ydbio.2009.06.015
  31. Ebarasi L, Ashraf S, Bierzynska A, Gee HY, McCarthy HJ, Lovric S, et al. Defects of CRB2 cause steroid-resistant nephrotic syndrome. Am J Hum Genet. 2015;96:153–161. doi:10.1016/j.ajhg.2014.11.014
  32. Möller-Kerutt A, Rodriguez-Gatica JE, Wacker K, Bhatia R, Siebrasse JP, Boon N, et al. Crumbs2 is an essential slit diaphragm protein of the renal filtration barrier. J Am Soc Nephrol. 2021;32(5):1053–1070. doi:10.1681/ASN.2020040476
  33. Tanoue A, Katayama K, Ito Y, Joh K, Toda M, Yasuma T, et al. Podocyte-specific Crb2 knockout mice develop focal segmental glomerulosclerosis. Sci Rep. 2021;11. doi:10.1038/s41598-021-92767-4
  34. Udagawa T, Yanagihara JT, Shimizu T, Mitsui A, Tsuji J, Morishita S, et al. Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2017;32:801–809. doi:10.1007/s00467-016-3548-7
  35. Kalyta K, Stelmaszczyk W, Szczęśniak D, Kotuła L, Dobosz P, Mroczek M. The spectrum of the heterozygous effect in biallelic Mendelian diseases—the symptomatic heterozygote issue. Genes (Basel). 2023;14(8):1562. doi:10.3390/genes14081562
  36. Morais S, Pereira M, Lau C, Gonçalves A, Monteiro C, Gonçalves M, et al. CalDAG-GEFI deficiency in a family with symptomatic heterozygous and homozygous carriers of a likely pathogenic variant in RASGRP2. Int J Mol Sci. 2021;22(22):12423. doi:10.3390/ijms222212423
  37. Silva RS, Carvalho B, Pedro J, Castro-Correia C, Carvalho D, Carvalho F, et al. Differences in hormonal levels between heterozygous CYP21A2 pathogenic variant carriers, non-carriers, and females with non-classic congenital hyperplasia. Arch Endocrinol Metab. 2022;66(2):168–175. doi:10.20945/2359-3997000000448
  38. Marek-Yagel D, Berkun Y, Padeh S, Abu A, Reznik-Wolf H, Livneh A, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60(6):1862–1866. doi:10.1002/art.24570
  39. Yang Q, Tang D, Gan C, Bai M, Song X, Jiang W, et al. Novel variants in CRB2 targeting the malfunction of slit diaphragm related to focal segmental glomerulosclerosis. Pediatr Nephrol. 2024;39(1):149–165. doi:10.1007/s00467-023-06095-y
  40. Udagawa T, Jo T, Yanagihara T, Shimizu A, Mitsui J, Tsuji S, et al. Altered expression of Crb2 in podocytes expands a variation of CRB2 mutations in steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2017;32(5):801–809. doi:10.1007/s00467-016-3548-7
  41. Colbert GB, Elrggal ME, Gaddy A, Madariaga HM, Lerma EV. Management of Hypertension in Diabetic Kidney Disease. J Clin Med Res. 2023;12(21):6868. doi:10.3390/jcm12216868
  42. Elrggal ME, Ahmed SMS, El Nahas M. Renin-Angiotensin-Aldosterone system blockade in diabetic kidney disease: A critical and contrarian point of view. Saudi J Kidney Dis Transpl. 2016;27(6):1103–1113. doi:10.4103/1319-2442.194649
  43. Colbert GB, Madariaga HM, Gaddy A, Elrggal ME, Lerma EV. Empagliflozin in Adults with Chronic Kidney Disease (CKD): Current Evidence and Place in Therapy. Ther Clin Risk Manag. 2023;19:133–142. doi:10.2147/TCRM.S382848
  44. Elkeraie A, Zyada R, Elrggal ME, Elrggal M. Safety of SGLT2 inhibitors in patients with different glomerular diseases treated with immunosuppressive therapies. Eur J Clin Pharmacol. 2023;79(7):961–966. doi:10.1007/s00228-023-03498-6
  45. Wheeler DC, Jongs N, Stefansson BV, Chertow GM, Greene T, Hou FF, et al. Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. Nephrol Dial Transplant. 2022;37(9):1647–1656. doi:10.1093/ndt/gfab335

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