Atypical Polycystic Kidney Disease in Individuals Heterozygous For Rare ALG8 Protein-truncating Variants

Introduction

Heterozygous ALG8 variants have previously been associated with polycystic liver disease (PLD) with or without kidney cysts. A clear-cut relationship between the application of polycystic kidney disease (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 PKD. 

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Methods

 We identified patients heterozygous for pathogenic (P) and likely pathogenic (LP) ALG8 (NM_024079.5) PTVs variants described in ClinVar from the Geisinger-Regeneron DiscovEHR MyCode study, an unselected health system-based cohort linked to electronic health records. Carriers of ALG8 PTV variants heterozygotes were matched 1:1 to non-heterozygote family members by age at the 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 abdominal ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). 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 a 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).

Conclusion

Our study demonstrates that individuals 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 variant heterozygotes are at increased risk of kidney failure.

Ben Apple, Gino Sartori, Kiran Chintam, Bryn Moore, William Triffo, Natasha Strande, Gurmukteshwar Singh, Tooraj Mirshahi, Alex Chang;

 Geisinger Commonwealth School of Medicine, Scranton, PA;  Department of Radiology, Geisinger, Danville, PA;  Kidney Health Research Institute, Geisinger, Danville, PA;  Department of Molecular and Functional Genomics, Geisinger, Danville, PA;  Department of Molecular and Functional Genetics, Geisinger, Danville, PA;