Low frequency of parental mosaicism in de novo COL4A5 mutations in X-linked Alport syndrome

Background: Alport syndrome is a progressive hereditary kidney disease clinically presenting with haematuria, proteinuria, and early onset end-stage renal disease, and often accompanied by hearing loss and ocular abnormalities. The inheritance is X-linked in the majority of families and caused by sequence variants in theCOL4A5gene encoding the alpha 5-chain of type-IV collagen. The proportion ofde novo COL4A5sequence variants in X-linked Alport syndrome has been reported between 12 and 15% in previous studies. Methods: In the present study we have systematically investigated the mosaic status of asymptomatic parents of six patients with X-linked Alport syndrome using next-generation sequencing of DNA extracted from different tissues. The deleteriousCOL4A5sequence variants in these patients were previously assumed to bede novo, based on Sanger sequencing of the parents. Results: A low-grade (1%) parental mosaicism was detected in only one out of six families (17%). In addition, in one out of six families (17%), we found that the mutational event probably occurred postzygotic. Conclusion: These findings highlight the importance of testing for mosaicism in unaffected parents of patients with sequence variants considered to bede novo, as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.