Detection of Cryptic Mosaicism in X-linked Alport Syndrome Prompts to Re-evaluate Living-donor Kidney Transplantation. Issue 11 (November 2020)

• Record Type: Journal Article
• Authors: Pinto, Anna Maria; Daga, Sergio; Fallerini, Chiara; Bruttini, Mirella; Baldassarri, Margherita; Giliberti, Annarita; Frullanti, Elisa; Guarnieri, Andrea; Garosi, Guido; Renieri, Alessandra
• Is Part Of: Transplantation. Volume 104:Issue 11(2020)
• Publication Date: 2020-11
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000003104
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: Alport syndrome is a hereditary nephropathy caused by mutations in collagen IV genes and characterized by ultrastructural lesions of the glomerular basement membrane. Some patients have a negative family history with apparently de novo mutations. Although somatic mosaicism has been postulated, as cryptic mosaicism cannot be detected from mutational screening on peripheral blood samples, cases in kidney-confined mosaic form have been missed. Methods: We report the case of a 24-year-old male patient with X-linked Alport syndrome diagnosis due to a COL4A5 pathogenic mutation (c.3334_3337dup [p.Gly1113Alafs * 25]). The same mutation had not been previously detected on a peripheral blood sample of maternal DNA. However, the mother, who was undertaking a clinical re-evaluation to take in consideration the possibility of a living-kidney transplantation, had experienced persistent microhematuria since the age of 10 years. Results: A next-generation sequencing approach performed on maternal DNA from both peripheral blood sample and urine-derived podocyte-lineage cells unmasked the COL4A5 mutation only in the podocyte-lineage cells. Conclusions: This finding unveils an early postzygotic event which can explain both the renal involvement and germline mosaicism. It changes the inheritance risk for each pregnancy raising it to 50% and underlines the need for different clinical management in the mother. This seems to indicate that a case-by-case more cautious approach is needed with mother-to-son kidney transplants. Abstract : Supplemental Digital Content is available in the text.