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.

Keywords: autosomal dominant polycystic kidney disease; chronic kidney disease; genetics; genotype-first; polycystic liver disease; renal cyst.

Figure 1.. Flowchart

Abbreviations: PTV (protein truncating variant), eGFR (estimated glomerular filtration rate), ICD (International Classification of Diseases)

Figure 2.. Radiologic Imaging of Families with ALG8 p.Arg364Ter Heterozygotes

Representative imaging collected from 19 ALG8 p. Arg364Ter heterozygotes from 9 families.

Figure 3.. Radiologic Imaging of a Family with ALG8 p.Arg179Ter Heterozygotes and an individual with ALG8 Arg41Ter

The images on the top and the bottom left show representative imaging from 3 ALG8 p.Arg179Ter heterozygotes from 2 families. The bottom right image is from an individual heterozygous for ALG8 Arg41Ter.