Open AccessLow frequency of parental mosaicism in de novo COL4A5 mutations in X‐linked Alport syndrome
Author(s) -
Helle Ole Magnus Bjorgaas,
Pedersen Torkild Høieggen,
Ousager Lilian Bomme,
Thomassen Mads,
Hertz Jens Michael
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1452
Subject(s) - alport syndrome , sanger sequencing , genetics , x linked recessive inheritance , disease , biology , x chromosome , mutation , gene , medicine , glomerulonephritis , kidney
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 the COL4A5 gene encoding the α5‐chain of type‐IV collagen. The proportion of de novo COL4A5 sequence 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 deleterious COL4A5 sequence variants in these patients were previously assumed to be de 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 be de novo , as it may have implications for the recurrence risk and thereby for the genetic counseling of the family.