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Publication Information
Affiliation
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; Department of Nephrology, Chongqing Municipal Hospital of Traditional Chinese Medicine, Chongqing 400021, China.; School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin 2, Ireland.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA; University Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.; Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.; Univ Brest, Inserm, UMR 1078, GGB, CHU Brest, F-29200 Brest, France.; Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Ophthalmology, Mayo Clinic, Rochester, MN 55905, USA.; Department of Nephrology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.; Department of Medical Laboratory Sciences, Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Sulaibikhat 90805, Kuwait; Department of Genetics and Bioinformatics, Dasman Diabetes Institute (DDI), Dasman 15462, Kuwait.; Renal Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.; Division of Nephrology, University of Alabama, Birmingham, AL 35294, USA; The Department of Veterans Affairs Medical Center, Birmingham, AL 35294, USA.; Renal Department, NHS Lothian - Royal Infirmary Edinburgh, Edinburgh, EH1 3EG, UK.; Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.; Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.; Kidney Genetics Group, Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, S10 2JF, UK; The Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, S10 2JF, UK.; Department of Nephrology, Beaumont Hospital and Department of Medicine Royal College of Surgeons in Ireland, Dublin 9, Ireland.; Division of Nephrology, Tufts Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA.; Univ Brest, Inserm, UMR 1078, GGB, CHU Brest, F-29200 Brest, France.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK; Renal Services, Newcastle Upon Tyne Hospitals NHS Foundation Trust, and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK.; Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: harris.peter@mayo.edu.
Authors
Senum Sarah R, Li Ying Sabrina M, Benson Katherine A, Joli Giancarlo, Olinger Eric, Lavu Sravanthi, Madsen Charles D, Gregory Adriana V, Neatu Ruxandra, Kline Timothy L, Audrézet Marie-Pierre, Outeda Patricia, Nau Cherie B, Meijer Esther, Ali Hamad, Steinman Theodore I, Mrug Michal, Phelan Paul J, Watnick Terry J, Peters Dorien J M, Ong Albert C M, Conlon Peter J, Perrone Ronald D, Cornec-Le Gall Emilie, Hogan Marie C, Torres Vicente E, Sayer John A, Harris Peter C
Studies
Abstract
Autosomal dominant polycystic kidney disease (ADPKD), characterized by progressive cyst formation/expansion, results in enlarged kidneys and often end stage kidney disease. ADPKD is genetically heterogeneous; PKD1 and PKD2 are the common loci (∼78% and ∼15% of families) and GANAB, DNAJB11, and ALG9 are minor genes. PKD is a ciliary-associated disease, a ciliopathy, and many syndromic ciliopathies have a PKD phenotype. In a multi-cohort/-site collaboration, we screened ADPKD-diagnosed families that were naive to genetic testing (n = 834) or for whom no PKD1 and PKD2 pathogenic variants had been identified (n = 381) with a PKD targeted next-generation sequencing panel (tNGS; n = 1,186) or whole-exome sequencing (WES; n = 29). We identified monoallelic IFT140 loss-of-function (LoF) variants in 12 multiplex families and 26 singletons (1.9% of naive families). IFT140 is a core component of the intraflagellar transport-complex A, responsible for retrograde ciliary trafficking and ciliary entry of membrane proteins; bi-allelic IFT140 variants cause the syndromic ciliopathy, short-rib thoracic dysplasia (SRTD9). The distinctive monoallelic phenotype is mild PKD with large cysts, limited kidney insufficiency, and few liver cysts. Analyses of the cystic kidney disease probands of Genomics England 100K showed that 2.1% had IFT140 LoF variants. Analysis of the UK Biobank cystic kidney disease group showed probands with IFT140 LoF variants as the third most common group, after PKD1 and PKD2. The proximity of IFT140 to PKD1 (∼0.5 Mb) in 16p13.3 can cause diagnostic confusion, and PKD1 variants could modify the IFT140 phenotype. Importantly, our studies link a ciliary structural protein to the ADPKD spectrum.