[en] [en] BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a common, inherited nephropathy often resulting in kidney failure. It is genetically heterogeneous; along with the major genes, PKD1 and PKD2, at least 8 others have been suggested. ALG8 pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while ALG9 has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear.
METHODS: We screened >3900 families with cystic kidneys and/or livers using global approaches to detect ALG8 or ALG9 pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100kGP (100kGP), UK Biobank (UKBB), and Mayo Clinic Biobank (MCBB)), were screened for ALG8/ALG9 pathogenic variants.
RESULTS: Multicenter screening of individuals with polycystic kidney and/or liver disease identified 51 (1.3%) ALG8 (7 multiplex) and 23 (0.6%) ALG9 (5 multiplex) families; frequencies that were ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had PKD1 and ALG8 pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (56%, >10 cysts), with greater median kidney and liver cyst numbers than controls. For ALG9, 78% had kidney cysts (27%, >10 cysts). Individuals with ALG8 mutations typically had mild cystic kidneys with limited enlargement. Liver cysts were common (71%) with enlarged livers (>2L) found in 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare.
CONCLUSIONS: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.
Disciplines :
Urology & nephrology
Author, co-author :
Jawaid, Tabinda ; Division of Nephrology and Hypertension
Elbarougy, Doaa E ; Division of Nephrology and Hypertension
Lavu, Sravanthi ; Division of Nephrology and Hypertension
Buia, Guillaume; Univ Brest, Inserm, UMR 1078, GGB, CHU Brest ; Centre de Références Maladies Rénales Hérédiatires de l'Enfant et de l'Adulte MARHEA, F-29200 Brest, France
Senum, Sarah R ; Division of Nephrology and Hypertension
Olinger, Eric ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University ; Center for Human Genetics, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Yang, Hana; Division of Nephrology and Hypertension
McDonnell, Shannon K ; Department of Quantitative Health Sciences
Bublitz, Joshua T; Department of Quantitative Health Sciences
Ma, Jun ; Division of Computational Biology
Audrézet, Marie-Pierre ; Univ Brest, Inserm, UMR 1078, GGB, CHU Brest ; Centre de Références Maladies Rénales Hérédiatires de l'Enfant et de l'Adulte MARHEA, F-29200 Brest, France
Madsen, Charles D ; Division of Nephrology and Hypertension
Schauer, Rachel S ; Division of Nephrology and Hypertension
Baker, Tracy A ; Division of Nephrology and Hypertension
Gregory, Adriana V ; Division of Nephrology and Hypertension
Orr, Sarah G ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University
Barroso-Gil, Miguel ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University
Neatu, Ruxandra ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University
Joli, Giancarlo; Division of Nephrology and Hypertension ; University Vita Salute San Raffaele, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy
Dahl, Neera K ; Division of Nephrology and Hypertension
Kline, Timothy L ; Department of Radiology
Gillion, Valentine ; Division of Nephrology, Cliniques Universitaires Saint-Luc and ; Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium ; European Reference Network for Rare Kidney Diseases (ERKNet
Dahan, Karin; European Reference Network for Rare Kidney Diseases (ERKNet ; Institute Pathology and Genetic, Center of Human Genetics, Charleroi, Belgium
Jouret, François ; Université de Liège - ULiège > Département des sciences cliniques > Néphrologie
Perrone, Ronald D ; Division of Nephrology, Tufts Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA
Steinman, Theodore I; Renal Division, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
Peters, Dorien J M ; Department of Human Genetics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Gitomer, Berenice Y ; Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Watnick, Terry J ; Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Coto, Eliecer; University of Oviedo, Dept of Medicine and RICORS-2040 (Kidney Disease), Oviedo, Spain
Chebib, Fouad T ; Division of Nephrology and Hypertension, Mayo Clinic, Jacksonville, FL, USA
Hogan, Marie C ; Division of Nephrology and Hypertension
Olson, Janet E ; Division of Epidemiology
Larson, Nicholas B ; Department of Quantitative Health Sciences
Ars, Elisabet ; Molecular Biology Laboratory, Fundació Puigvert, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), RICORS2040 (Kidney Disease), Universitat Autònoma de Barcelona, Barcelona, 08025 Catalonia, Spain
Halbritter, Jan ; Department of Nephrology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin ; Division of Nephrology, Department of Internal Medicine, University of Leipzig Medical Center, Leipzig, Germany
Demoulin, Nathalie ; Division of Nephrology, Cliniques Universitaires Saint-Luc and ; Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium ; European Reference Network for Rare Kidney Diseases (ERKNet
Torres, Vicente E ; Division of Nephrology and Hypertension
Sayer, John A ; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University ; Renal Services, Newcastle Upon Tyne Hospitals NHS Foundation Trust, and NIHR Newcastle Biomedical Research Centre, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK
Cornec-Le Gall, Emilie ; Univ Brest, Inserm, UMR 1078, GGB, CHU Brest ; Centre de Références Maladies Rénales Hérédiatires de l'Enfant et de l'Adulte MARHEA, F-29200 Brest, France
Harris, Peter C ; Division of Nephrology and Hypertension ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA
Genomics England Research Consortium, UK Biobank, HALT PKD, DIPAK, TAME PKD, Genkyst studies, Mayo Clinic Biobank, and Regeneron Genetics Center
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