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

Ole Magnus Bjorgaas Helle, Torkild Høieggen Pedersen, Lilian Bomme Ousager, Mads Thomassen, Jens Michael Hertz

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Abstract

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.

Original languageEnglish
Article numbere1452
JournalMolecular Genetics & Genomic Medicine
Volume8
Issue number10
Number of pages7
ISSN2324-9269
DOIs
Publication statusPublished - 1. Oct 2020

Keywords

  • Alport syndrome
  • COL4A5
  • de novo mutation
  • mosaicism

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