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Publication Information
Affiliation
Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Department of Nephrology, Centre Hospitalier Universitaire de Brest, Université de Brest, Brest, France; National Institute of Health and Medical Sciences, INSERM U1078, Brest, France.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Kidney Genetics Group, Academic Nephrology Unit, University of Sheffield, Sheffield, UK.; Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Nephrology and Hypertension, Cleveland Clinic, Cleveland, Ohio, USA.; Renal Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.; Division of Nephrology, University of Chicago School of Medicine, Chicago, Illinois, USA; Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.; Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA.; Division of Nephrology, Tufts University Medical Center, Boston, Massachusetts, USA.; Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: harris.peter@mayo.edu.
Authors
Hopp Katharina, Cornec-Le Gall Emilie, Senum Sarah R, Te Paske Iris B A W, Raj Sonam, Lavu Sravanthi, Baheti Saurabh, Edwards Marie E, Madsen Charles D, Heyer Christina M, Ong Albert C M, Bae Kyongtae T, Fatica Richard, Steinman Theodore I, Chapman Arlene B, Gitomer Berenice, Perrone Ronald D, Rahbari-Oskoui Frederic F, Torres Vicente E, Harris Peter C
Studies
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is an inherited, progressive nephropathy accounting for 4-10% of end stage renal disease worldwide. PKD1 and PKD2 are the most common disease loci, but even accounting for other genetic causes, about 7% of families remain unresolved. Typically, these unsolved cases have relatively mild kidney disease and often have a negative family history. Mosaicism, due to de novo mutation in the early embryo, has rarely been identified by conventional genetic analysis of ADPKD families. Here we screened for mosaicism by employing two next generation sequencing screens, specific analysis of PKD1 and PKD2 employing long-range polymerase chain reaction, or targeted capture of cystogenes. We characterized mosaicism in 20 ADPKD families; the pathogenic variant was transmitted to the next generation in five families and sporadic in 15. The mosaic pathogenic variant was newly discovered by next generation sequencing in 13 families, and these methods precisely quantified the level of mosaicism in all. All of the mosaic cases had PKD1 mutations, 14 were deletions or insertions, and 16 occurred in females. Analysis of kidney size and function showed the mosaic cases had milder disease than a control PKD1 population, but only a few had clearly asymmetric disease. Thus, in a typical ADPKD population, readily detectable mosaicism by next generation sequencing accounts for about 1% of cases, and about 10% of genetically unresolved cases with an uncertain family history. Hence, identification of mosaicism is important to fully characterize ADPKD populations and provides informed prognostic information.