Individuals heterozygous for ALG8 protein-truncating variants are at increased risk of a mild cystic kidney disease.

Abstract

ALG8 protein-truncating variants (PTVs) have previously been described in patients with polycystic liver disease and in some cases cystic kidney disease. Given a lack of well-controlled studies, we determined whether individuals heterozygous for ALG8 PTVs are at increased risk of cystic kidney disease in a large, unselected health system-based observational cohort linked to electronic health records in Pennsylvania (Geisinger-Regeneron DiscovEHR MyCode study). Out of 174,172 patients, 236 were identified with ALG8 PTVs. Using ICD-based outcomes, patients with these variants were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42, 95% confidence interval: 1.53-3.85), cystic kidney disease (3.03, 1.26-7.31), and nephrolithiasis (1.89, 1.96-2.97). To confirm this finding, blinded radiology review of computed tomography and magnetic resonance imaging studies was completed in a matched cohort of 52 thirty-plus year old ALG8 PTV heterozygotes and related non-heterozygotes. ALG8 PTV heterozygotes were significantly more likely to have cystic kidney disease, defined as four or more kidney cysts (57.7% vs. 7.7%), or bilateral kidney cysts (69.2% vs. 15.4%), but not one or more liver cyst (11.5% vs. 7.7%). In publicly available UK Biobank data, ALG8 PTV heterozygotes were at significantly increased risk of ICD code N28 (other disorders of kidney/ureter) (3.85% vs. 1.33%). ALG8 PTVs were not associated with chronic kidney disease or kidney failure in the MyCode study or the UK Biobank data. Thus, PTVs in ALG8 result in increased risk of a mild cystic kidney disease phenotype.

• Authors: Benjamin Apple, Gino Sartori, Bryn Moore, Kiran Chintam, Gurmukteshwar Singh, Prince Mohan Anand, Natasha T Strande, Tooraj Mirshahi, William Triffo, Alexander R Chang
• Journal: Kidney international (Kidney Int) Vol. 103 Issue 3 Pg. 607-615 (03 2023) ISSN: 1523-1755 [Electronic] United States
• PMID: 36574950 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• ALG8 protein, human
• Glucosyltransferases

Topics

• Humans
• Polycystic Kidney Diseases (pathology)
• Kidney (pathology)
• Cysts (genetics)
• Liver Diseases (diagnosis, epidemiology, genetics)
• Polycystic Kidney, Autosomal Dominant (diagnosis, epidemiology, genetics)
• Glucosyltransferases