Somatic mutation in autosomal dominant polycystic kidney disease revealed by deep sequencing human kidney cysts
Autosomal Dominant Polycystic Kidney Disease (ADPKD) results in progressive cysts that lead to kidney failure, and is caused by heterozygous germline variants in PKD1 or PKD2. Cyst pathogenesis is not definitively understood. Somatic second-hit mutations have been implicated in cyst pathogenesis, though technical sequencing challenges have limited investigation. We used unique molecular identifiers, high-depth massively parallel sequencing and custom analysis techniques to identify somatic second-hit mutations in 24 whole cysts from disparate regions of six human ADPKD kidneys, utilising replicate samples and orthogonal confirmation. Average depth of coverage of 1166 error-corrected reads for PKD1 and 539 reads for PKD2 was obtained. 58% (14/24) of cysts had a detectable PKD1 somatic variant, with 5/6 participants having at least one cyst with a somatic variant. We demonstrate that low-frequency somatic mutations are detectable in a proportion of cysts from end-stage ADPKD human kidneys. Further studies are required to understand the drivers of this somatic mutation.
Authors
- Amali Mallawaarachchi (ORCID: https://orcid.org/0000-0002-1229-1701)
- Paul Snelling (ORCID: https://orcid.org/0000-0003-1219-9603)
- Sarah R. Senum (ORCID: https://orcid.org/0000-0002-5489-9117)
- Gopala K. Rangan (ORCID: https://orcid.org/0000-0002-2147-0998)
- Mike Utsiwegota
- Jane Mawson
- Jerome Laurence (ORCID: https://orcid.org/0000-0002-1123-0122)
- Robert Salomon (ORCID: https://orcid.org/0000-0003-4504-2901)
- Yvonne Hort
- Scott Leslie (ORCID: https://orcid.org/0000-0001-9848-969X)
- Mark J. Cowley (ORCID: https://orcid.org/0000-0002-9519-5714)
- Laura Wedd
- Lyndal Anderson (ORCID: https://orcid.org/0000-0002-9405-8195)
- Kitty Lo (ORCID: https://orcid.org/0000-0002-9392-512X)
- Wenhan Chen
- Mojgan Toumari
- John Shine
- Timothy J. Furlong
Institutions
- The University of Sydney (AU)
- New South Wales Department of Health (AU)
- Garvan Institute of Medical Research (AU)
- Royal Prince Alfred Hospital (AU)
- Cancer Institute of New South Wales (AU)
- Westmead Hospital (AU)
- UNSW Sydney (AU)
- Chris O’Brien Lifehouse (AU)
- Children's Cancer Institute Australia (AU)
- Westmead Institute for Medical Research (AU)
- Mayo Clinic in Florida (US)
- Murdoch Children's Research Institute (AU)
Publication Details
- Journal
- npj Genomic Medicine
- Published
- 2024-12-19
- DOI
- https://doi.org/10.1038/s41525-024-00452-6
- Citations
- 2
- Primary Topic
- Genetic and Kidney Cyst Diseases
- Type
- article
- Field-Weighted Citation Impact
- 1.10
Funders
- PKD Foundation
- Sylvia and Charles Viertel Charitable Foundation
- Jerry M. Lewis, M.D. Mental Health Research Foundation
- Cancer Australia
- Royal Australasian College of Physicians