Atypical Polycystic Kidney Disease in Individuals Heterozygous for ALG8 Protein-truncating variants

Background Heterozygous ALG8 variants have previously been associated with polycystic liver disease (PLD) with or without kidney cysts. A clear-cut relationship between application of PKD diagnostic criteria and kidney manifestations of ALG8 variants remains to be described. We therefore sought to determine whether ALG8 protein-truncating variant (PTV) heterozygotes are at increased risk of polycystic kidney disease (PKD). Methods We identified participants heterozygous for pathogenic (P) and likely pathogenic (LP) ALG8 (NM_024079.5) PTVs described in ClinVar from the Geisinger-Regeneron DiscovEHR MyCode study, an unselected health system-based cohort linked to electronic health records. ALG8 PTV heterozygotes were matched 1:1 to non-heterozygote family members by age at time of imaging (within 10 years) and sex. Phenotypes were assessed by International Classification of Disease (ICD) codes, chart review, and imaging, which was reviewed by a blinded radiologist. Imaging diagnosis of PKD was defined as ≥4 kidney cysts on an abdominal ultrasound or computed tomography. Secondary outcomes included bilateral renal cysts, and ≥1 liver cyst. Results Out of 174,418 participants in MyCode,103 participants (mean age 56.7 years) were heterozygous for an ALG8 P/LP variant: p.Arg364Ter (n=86), p.Arg41Ter (n=7), p.Arg179Ter (n=9), and c.368+2T>G (n=2). None of the ALG8 P/LP variant heterozygotes had an ICD diagnosis of PKD or PLD. Out of 51 participants ≥40 years of age with available imaging, 51% had ≥4 renal cysts and 14% had ≥1 liver cyst. After matching 23 ALG8 P/LP variant heterozygotes with 23 related non-heterozygotes by age and imaging modality, ALG8 P/LP heterozygotes had higher prevalence of 4+ kidney cysts (48% versus 9% in non-heterozygotes; p=0.007) and bilateral kidney cysts (61% vs. 17%; p=0.006). Conclusions Our study demonstrates that patients heterozygous for ALG8 P/LP variants are at increased risk of PKD on imaging but not by ICD diagnosis codes. Additional studies are needed to determine whether ALG8 P/LP heterozygotes are at increased risk of kidney failure.