Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. 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 eight 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 100K Genomics Project, UK Biobank, 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 approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine 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 (50%, >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 of 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, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

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Journal
Journal of the American Society of Nephrology
Published
2025-02-03
DOI
https://doi.org/10.1681/asn.0000000613
Citations
8
Primary Topic
Genetic and Kidney Cyst Diseases
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article
Field-Weighted Citation Impact
14.54

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article

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants

Peter C. Harris, Nathalie Demoulin, Nicholas Bradley Larson, Dorien J.M. Peters et al.
8 citations
Journal of the American Society of Nephrology
Genetic and Kidney Cyst Diseases
14.54
article

Characterization of the Cystic Phenotype Associated with Monoallelic ALG8 and ALG9 Pathogenic Variants

Peter C. Harris, Nathalie Demoulin, Nicholas Bradley Larson, Dorien J.M. Peters, Jan Halbritter, Timothy L. Kline, Eliécer Coto, Adriana Gregory, Karin Dahan, Fouad T. Chebib, Sarah Orr, Neera K. Dahl, Sarah R. Senum, John Andrew Sayer, Ruxandra Neatu, Charles D. Madsen, Miguel Barroso‐Gil, Joshua T. Bublitz, Giancarlo Joli, Elisabet Ars, Marie‐Pierre Audrézet, Eric Olinger, Vicente E. Torres, Sravanthi Lavu, Valentine Gillion, François Jouret, Ronald D. Perrone, Terry Watnick, Berenice Y. Gitomer, Theodore I. Steinman, Shannon K. McDonnell, Janet E. Olson, Tacey L. Baker, Marie C. Hogan, Hana Yang, Émilie Cornec-Le Gall, Doaa E. Elbarougy, Jun Ma, R. Schauer, Tabinda Jawaid, Guillaume Buia
article en
8 citations

Abstract

Key Points Loss-of-function ALG8 and ALG9 variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. ALG8 pathogenic variants sometimes resulted in severe polycystic liver disease. 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 eight 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 100K Genomics Project, UK Biobank, 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 approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine 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 (50%, >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 of 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, CKD or kidney failure were rare. Conclusions ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.

Journal of the American Society of NephrologyVol. 36(6)
Tufts University (US), Universitat Autònoma de Barcelona (ES), University of Maryland, Baltimore (US), Tufts Medical Center (US), Cliniques Universitaires Saint-Luc (BE), Beth Israel Deaconess Medical Center (US), Mayo Clinic (US), Vita-Salute San Raffaele University (IT), Inserm (FR), University of Liège (BE), Université de Bretagne Occidentale (FR), Universidad de Oviedo (ES), Leiden University Medical Center (NL), WinnMed (US), Humboldt-Universität zu Berlin (DE), Clinical Research Institute (US), Institute of Pathology and Genetics (BE), Hôpital d'Enfants (FR), Centre Hospitalier Régional Universitaire de Brest (FR), NIHR Newcastle Biomedical Research Centre (GB), Hypertension Institute (US), ERN GUARD-Heart (NL), Puigvert Foundation (ES), Mayo Clinic in Florida (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele (IT), ERKNet, University of Colorado Anschutz Medical Campus (US), Freie Universität Berlin (DE), University of Newcastle Australia (AU), Charité - Universitätsmedizin Berlin (DE), Newcastle University (GB), Leipzig University (DE)
PKD Foundation, American Society of Nephrology, Sanofi, Mayo Foundation for Medical Education and Research, Regeneron Pharmaceuticals, Kidney Research UK, Agence Nationale de la Recherche, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Universiteit Leiden, Erasmus Medisch Centrum, Leids Universitair Medisch Centrum, Universitair Medisch Centrum Groningen, European Rare Kidney Disease Reference Network, Medical Research Council, National Institute of Diabetes and Digestive and Kidney Diseases
Good health and well-being
Openalex Percentile: Top 1%
Genetic and Kidney Cyst Diseases
14.54
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