Implications of a Genetic Etiology for Renal Transplant: Early-Onset Alport Syndrome with a Novel Mutation

Abstract

Alport's syndrome (AS) is a rare disorder characterized by a triad of deafness, progressive renal dysfunction, and ocular abnormalities. We presented a patient of early onset AS with a novel frameshift pathogenic variant in the COL4A5 gene and discuss the utility of genetic testing in the family as well as for the transplant recipient. The patient was a 17-year-old adolescent male with end-stage renal disease (ESRD) and hearing loss. In the setting of ESRD, since hearing loss and anterior lenticonus was detected on an ophthalmologic exam, AS was suspected. On genetic testing, a novel hemizygous frameshift variant was identified in the COL4A5 gene (c.1392del (p.Asp464GlufsTer10)), which was also segregated in the family. In this report, we discussed the early severe presentation, typical ocular findings, genotype–phenotype correlation, and implications of genetic testing for renal transplant. We also explored the challenges of genetic testing in developing countries and the potential of pharmacogenomics.

Keywords

COL4A5 - deafness - genetic - ocular - kidney transplantation

• References

• 1 Hasstedt SJ, Atkin CL. X-linked inheritance of Alport syndrome: family P revisited. Am J Hum Genet 1983; 35 (06) 1241-1251
• 2 Pajari H, Kääriäinen H, Muhonen T, Koskimies O. Alport's syndrome in 78 patients: epidemiological and clinical study. Acta Paediatr 1996; 85 (11) 1300-1306
• 3 Persson U, Hertz JM, Wieslander J, Segelmark M. Alport syndrome in southern Sweden. Clin Nephrol 2005; 64 (02) 85-90
• 4 Hertz JM, Thomassen M, Storey H, Flinter F. Clinical utility gene card for: Alport syndrome—update 2014. Eur J Hum Genet 2015; 23 (09)
• 5 United States Renal Data System (USRDS). Accessed May 23, 2020 at: https://www.usrds.org/
• 6 Kashtan CE. Renal transplantation in patients with Alport syndrome: patient selection, outcomes, and donor evaluation. Int J Nephrol Renovasc Dis 2018; 11: 267-270
• 7 Bekheirnia MR, Reed B, Gregory MC. et al. Genotype-phenotype correlation in X-linked Alport syndrome. J Am Soc Nephrol 2010; 21 (05) 876-883
• 8 Lemmink HH, Schröder CH, Monnens LA, Smeets HJ. The clinical spectrum of type IV collagen mutations. Hum Mutat 1997; 9 (06) 477-499
• 9 Jais JP, Knebelmann B, Giatras I. et al. X-linked Alport syndrome: natural history in 195 families and genotype- phenotype correlations in males. J Am Soc Nephrol 2000; 11 (04) 649-657
• 10 Jais JP, Knebelmann B, Giatras I. et al. X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a “European Community Alport Syndrome Concerted Action” study. J Am Soc Nephrol 2003; 14 (10) 2603-2610
• 11 Miller KE, Hoyt R, Rust S, Doerschuk R, Huang Y, Lin SM. The financial impact of genetic diseases in a pediatric accountable care organization. Front Public Health 2020; 8: 58
• 12 Proesmans W, Knockaert H, Trouet D. Enalapril in paediatric patients with Alport syndrome: 2 years' experience. Eur J Pediatr 2000; 159 (06) 430-433
• 13 Gross O, Licht C, Anders HJ. et al; Study Group Members of the Gesellschaft für Pädiatrische Nephrologie. Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectancy. Kidney Int 2012; 81 (05) 494-501
• 14 Mallett A, Tang W, Clayton PA. et al. End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases. Nephrol Dial Transplant 2014; 29 (12) 2277-2286
• 15 Gillion V, Dahan K, Cosyns JP. et al. Genotype and outcome after kidney transplantation in Alport syndrome. Kidney Int Rep 2018; 3 (03) 652-660