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

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 8 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 100kGP (100kGP), UK Biobank (UKBB), 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 ∼10x and ∼24x greater than non-polycystic kidney disease (PKD) controls. Analysis of individuals with PKD phenotypes in 100kGP, UKBB, and MCBB identified 9 ALG8 (0.39%) and 9 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 (56%, >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 11/62 patients although surgical intervention was rare. The ALG9 kidney phenotype was also of mild cystic kidneys but enlarged livers were rare; for both genes chronic kidney disease or kidney failure were rare. Conclusions: ALG8 and ALG9 are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.