[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
Cornec-Le Gall E, Alam A, Perrone RD: Autosomal dominant polycystic kidney disease. Lancet, 393: 919-935, 2019 10.1016/S0140-6736(18)32782-X
Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, et al.: Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol, 20: 205-212, 2009 10.1681/ASN.2008050507 PMC2615723
Pei Y, Hwang YH, Conklin J, Sundsbak JL, Heyer CM, Chan W, et al.: Imaging-based diagnosis of autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 26: 746-753, 2015 10.1681/ASN.2014030297 PMC4341484
Dalgaard OZ: Bilateral polycystic disease of the kidneys: A follow-up of two hundred and eighty-four patients and their families. Acta Med Scand, 328: 1-255, 1957
Suwabe T, Shukoor S, Chamberlain AM, Killian JM, King BF, Edwards M, et al.: Epidemiology of Autosomal Dominant Polycystic Kidney Disease in Olmsted County. Clin J Am Soc Nephrol, 15: 69-79, 2020 10.2215/CJN.05900519 PMC6946081
Chang AR, Moore BS, Luo JZ, Sartori G, Fang B, Jacobs S, et al.: Exome Sequencing of a Clinical Population for Autosomal Dominant Polycystic Kidney Disease. JAMA, 328: 2412-2421, 2022 10.1001/jama.2022.22847 PMC9856880
Johansen KL, Chertow GM, Foley RN, Gilbertson DT, Herzog CA, Ishani A, et al.: US Renal Data System 2020 Annual Data Report: Epidemiology of Kidney Disease in the United States. Am J Kidney Dis. Apr;77(4 Suppl 1):A7-A8, 2021, doi: 10.1053/j.ajkd.2021.01.002. PMID: 33752804; PMCID: PMC8148988.
Chebib FT, Jung Y, Heyer CM, Irazabal MV, Hogan MC, Harris PC, et al.: Effect of genotype on the severity and volume progression of polycystic liver disease in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant, 31: 952-960, 2016 10.1093/ndt/gfw008 PMC4876970
Lavu S, Vaughan LE, Senum SR, Kline TL, Chapman AB, Perrone RD, et al.: The value of genotypic and imaging information to predict functional and structural outcomes in ADPKD. JCI Insight, 5: e138724, 2020 10.1172/jci.insight.138724 PMC7455088
Cornec-Le Gall E, Audrezet MP, Rousseau A, Hourmant M, Renaudineau E, Charasse C, et al.: The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol, 27: 942-951, 2016 10.1681/ASN.2015010016 PMC4769200
McConnachie DJ, Stow JL, Mallett AJ: Ciliopathies and the Kidney: A Review. Am J Kidney Dis, 77: 410-419, 2021 10.1053/j.ajkd.2020.08.012
Derderian C, Canales GI, Reiter JF: Seriously cilia: A tiny organelle illuminates evolution, disease, and intercellular communication. Dev Cell, 58: 1333-1349, 2023 10.1016/j.devcel.2023.06.013
Hu J, Harris PC: Regulation of polycystin expression, maturation and trafficking. Cell Signal, 72: 109630, 2020 10.1016/j.cellsig.2020.109630 PMC7269868
Fedeles SV, Tian X, Gallagher AR, Mitobe M, Nishio S, Lee SH, et al.: A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat Genet, 43: 639-647, 2011 10.1038/ng.860 PMC3547075
Lemoine H, Raud L, Foulquier F, Sayer JA, Lambert B, Olinger E, et al.: Monoallelic pathogenic ALG5 variants cause atypical polycystic kidney disease and interstitial fibrosis. Am J Hum Genet, 109: 1484-1499, 2022 10.1016/j.ajhg.2022.06.013 PMC9388391
Boulogne F, Claus LR, Wiersma H, Oelen R, Schukking F, de Klein N, et al.: KidneyNetwork: using kidney-derived gene expression data to predict and prioritize novel genes involved in kidney disease. Eur J Hum Genet, 2023 10.1038/s41431-023-01296-x
Apple B, Sartori G, Moore B, Chintam K, Singh G, Anand PM, et al.: Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease. Kidney Int, 103: 607-615, 2023 10.1016/j.kint.2022.11.025
Besse W, Chang AR, Luo JZ, Triffo WJ, Moore BS, Gulati A, et al.: ALG9 Mutation Carriers Develop Kidney and Liver Cysts. J Am Soc Nephrol, 30: 2091-2102, 2019 10.1681/ASN.2019030298 PMC6830805
Cornec-Le Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, et al.: Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. Am J Hum Genet, 102: 832-844, 2018 10.1016/j.ajhg.2018.03.013 PMC5986722
Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, et al.: Mutations in GANAB, Encoding the Glucosidase IIalpha Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. Am J Hum Genet, 98: 1193-1207, 2016 10.1016/j.ajhg.2016.05.004 PMC4908191
Senum SR, Li YSM, Benson KA, Joli G, Olinger E, Lavu S, et al.: Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype. Am J Hum Genet, 109: 136-156, 2022 10.1016/j.ajhg.2021.11.016 PMC8764120
Claus LR, Chen C, Stallworth J, Turner JL, Slaats GG, Hawks AL, et al.: Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease. Kidney Int, 104: 995-1007, 2023 10.1016/j.kint.2023.07.021 PMC10592035
Huynh VT, Audrezet MP, Sayer JA, Ong AC, Lefevre S, Le Brun V, et al.: Clinical spectrum, prognosis and estimated prevalence of DNAJB11-kidney disease. Kidney Int, 98: 476-487, 2020 10.1016/j.kint.2020.02.022 PMC9749391
Chantret I, Dancourt J, Dupré T, Delenda C, Bucher S, Vuillaumier-Barrot S, et al.: A deficiency in dolichyl-P-glucose:Glc1Man9GlcNAc2-PP-dolichyl alpha3-glucosyltransferase defines a new subtype of congenital disorders of glycosylation. J Biol Chem, 278: 9962-9971, 2003 10.1074/jbc.M211950200
Frank CG, Grubenmann CE, Eyaid W, Berger EG, Aebi M, Hennet T: Identification and functional analysis of a defect in the human ALG9 gene: definition of congenital disorder of glycosylation type IL. Am J Hum Genet, 75: 146-150, 2004 10.1086/422367 PMC1181998
Boerrigter MM, Te Morsche RHM, Venselaar H, Pastoors N, Geerts AM, Hoorens A, et al.: Novel α-1,3-Glucosyltransferase Variants and Their Broad Clinical Polycystic Liver Disease Spectrum. Genes (Basel), 14, 2023 10.3390/genes14081652 PMC10454741
Yu CC, Lee AF, Kohl S, Lin MY, Cheng SM, Hung CC, et al.: PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan. NPJ Genom Med, 7: 40, 2022 10.1038/s41525-022-00309-w PMC9249874
Lanktree MB, Haghighi A, Guiard E, Iliuta IA, Song X, Harris PC, et al.: Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J Am Soc Nephrol, 29: 2593-2600, 2018 10.1681/ASN.2018050493 PMC6171271
Schönauer R, Baatz S, Nemitz-Kliemchen M, Frank V, Petzold F, Sewerin S, et al.: Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes. Genet Med, 22: 1374-1383, 2020 10.1038/s41436-020-0816-3 PMC7394878
Kline TL, Korfiatis P, Edwards ME, Warner JD, Irazabal MV, King BF, et al.: Automatic total kidney volume measurement on follow-up magnetic resonance images to facilitate monitoring of autosomal dominant polycystic kidney disease progression. Nephrol Dial Transplant, 31: 241-248, 2016 10.1093/ndt/gfv314 PMC4725388
Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al.: Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol, 26: 160-172, 2015 10.1681/asn.2013101138 PMC4279733
Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al.: New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. N Engl J Med, 385: 1737-1749, 2021 10.1056/NEJMoa2102953 PMC8822996
Wang Q, Dhindsa RS, Carss K, Harper AR, Nag A, Tachmazidou I, et al.: Rare variant contribution to human disease in 281,104 UK Biobank exomes. Nature, 597: 527-532, 2021 10.1038/s41586-021-03855-y
Gunay-Aygun M, Turkbey BI, Bryant J, Daryanani KT, Gerstein MT, Piwnica-Worms K, et al.: Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease. Mol Genet Metab, 104: 677-681, 2011 10.1016/j.ymgme.2011.09.001 PMC3224207
Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al.: Imaging classification of autosomal dominant polycystic kidney disease: a simple model for selecting patients for clinical trials. J Am Soc Nephrol, 26: 160-172, 2015 10.1681/ASN.2013101138 PMC4279733
Rule AD, Sasiwimonphan K, Lieske JC, Keddis MT, Torres VE, Vrtiska TJ: Characteristics of renal cystic and solid lesions based on contrast-enhanced computed tomography of potential kidney donors. Am J Kidney Dis, 59: 611-618, 2012 10.1053/j.ajkd.2011.12.022 PMC3328591
Suwabe T, Chamberlain AM, Killian JM, King BF, Gregory AV, Madsen CD, et al.: Epidemiology of autosomal-dominant polycystic liver disease in Olmsted county. JHEP Rep, 2: 100166, 2020 10.1016/j.jhepr.2020.100166 PMC7593615
Ali H, Al-Mulla F, Hussain N, Naim M, Asbeutah AM, AlSahow A, et al.: PKD1 Duplicated regions limit clinical Utility of Whole Exome Sequencing for Genetic Diagnosis of Autosomal Dominant Polycystic Kidney Disease. Sci Rep, 9: 4141, 2019 10.1038/s41598-019-40761-w PMC6412018
Sparks SE, Krasnewich DM. Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview. 2005 Aug 15 [updated 2017 Jan 12]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301507.
Haeuptle MA, Hennet T: Congenital disorders of glycosylation: an update on defects affecting the biosynthesis of dolichol-linked oligosaccharides. Hum Mutat, 30: 1628-1641, 2009 10.1002/humu.21126
Schollen E, Frank CG, Keldermans L, Reyntjens R, Grubenmann CE, Clayton PT, et al.: Clinical and molecular features of three patients with congenital disorders of glycosylation type Ih (CDG-Ih) (ALG8 deficiency). J Med Genet, 41: 550-556, 2004 10.1136/jmg.2003.016923 PMC1735831
Tham E, Eklund EA, Hammarsjö A, Bengtson P, Geiberger S, Lagerstedt-Robinson K, et al.: A novel phenotype in N-glycosylation disorders: Gillessen-Kaesbach-Nishimura skeletal dysplasia due to pathogenic variants in ALG9. Eur J Hum Genet, 24: 198-207, 2016 10.1038/ejhg.2015.91 PMC4717212
Weinstein M, Schollen E, Matthijs G, Neupert C, Hennet T, Grubenmann CE, et al.: CDG-IL: an infant with a novel mutation in the ALG9 gene and additional phenotypic features. Am J Med Genet A, 136: 194-197, 2005 10.1002/ajmg.a.30851
Ariza M, Alvarez V, Marin R, Aguado S, Lopez-Larrea C, Alvarez J, et al.: A family with a milder form of adult dominant polycystic kidney disease not linked to the PKD1 (16p) or PKD2 (4q) genes. J Med Genet, 34: 587-589, 1997
Paul BM, Consugar MB, Ryan Lee M, Sundsbak JL, Heyer CM, Rossetti S, et al.: Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. Kidney Int 85: 383-392, 2014 10.1038/ki.2013.227,ki2013227 [pii]
