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

Abstract

Loss-of-function <i>ALG8</i> and <i>ALG9</i> variants were enriched in polycystic kidney/liver groups and International Classification of Diseases–coded cystic individuals in population cohorts. The ALG8 and ALG9 kidney phenotypes were usually mild to moderate, and lower eGFR or kidney failure was rare. <i>ALG8</i> pathogenic variants sometimes resulted in severe polycystic liver disease. 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, <i>PKD1</i> and <i>PKD2</i>, at least eight others have been suggested. <i>ALG8</i> pathogenic variants have been associated with autosomal dominant polycystic liver disease and implicated in ADPKD, while <i>ALG9</i> has been suggested as an ADPKD gene, but details of the phenotypes and penetrance are unclear. We screened >3900 families with cystic kidneys and/or livers using global approaches to detect <i>ALG8</i> or <i>ALG9</i> pathogenic variants. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) were screened for <i>ALG8</i>/<i>ALG9</i> pathogenic variants. 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 approximately 10× and approximately 24× greater than nonpolycystic kidney disease controls. Analysis of individuals with polycystic kidney disease phenotypes in 100K Genomics Project, UK Biobank, and MCBB identified nine ALG8 (0.39%) and nine ALG9 (0.39%) families, an enriched frequency over controls. Two individuals had <i>PKD1</i> and <i>ALG8</i> pathogenic changes. Eighty-nine percent of individuals with ALG8 mutations with imaging in the entire MCBB had kidney cysts (50%, >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 of 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, CKD or kidney failure were rare. <i>ALG8</i> and <i>ALG9</i> are defined as cystic kidney/liver genes but with limited penetrance for lower eGFR.