Renal Macrocystic Disease

Gene: ALG8

Green List (high evidence)

2023 Paper:
236 individuals identified with ALG8 protein-truncating variants. Patients were significantly at increased risk of having any kidney/liver cyst diagnosis (Odds Ratio 2.42), cystic kidney disease (OR 3.03), and nephrolithiasis (OR 1.89). 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%).

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.

Created: 6 Sep 2024, 12:34 a.m. | Last Modified: 6 Sep 2024, 12:34 a.m.

Panel Version: 0.70

Based on similar ALG genes, the CLINGEN review is discrepant to their review on other similar ALG genes with similar genetic and experimental evidence. Given patients present with PLD with kidney cysts, decision made that evidence is sufficient for PanelApp for classification as GREEN.

CLINGEN assessed as LIMITED (2020)
Monoallelic ALG8 pathogenic variants were first reported in relation to autosomal dominant polycystic liver disease (ADPLD) in 2017 (Besse et al., PMID: 28375157). Of note, biallelic ALG8 pathogenic variants have been associated with congenital disorder of glycosylation, type Ih (CDG-1h; OMIM #608104). Given that ALG8-associated ADPLD and ALG8-associated CDG-1h have different inheritance modes and phenotypic manifestations, we have split the two disease entities. As noted above, here we only curate the association between ALG8 and ADPLD. At least 3 variants (2 nonsense, 1 splice) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, population-level data, and experimental data. Variants in this gene have been reported in at least 6 probands in 2 publications (PMID: 28375157; PMID: 32457805). This gene-disease association is supported by in vitro functional assays showing reduced maturation of polycystin 1 in ALG8 null cells. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.

Created: 25 Nov 2022, 4:32 a.m. | Last Modified: 25 Nov 2022, 4:32 a.m.

Panel Version: 0.57

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Polycystic liver disease 3 with or without kidney cysts, MIM# 617874

Publications

• PMID: 36574950