Submission Details

The ALG8 gene is located on chromosome 11 at q14.1 and encodes the protein alpha-1,3 glucosyltransferase. It is involved in N-linked glycosylation of proteins, catalyzing the addition of a second glucose to lipid-linked oligosaccharides, a key step in post-translational protein modification.

Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their inheritance pattern and phenotypic spectrum. Therefore, the following disease entities have been split into two disease entities: polycystic liver disease 3 with or without kidney cysts (OMIM:617874) and congenital disorder of glycosylation, type Ih (CDG-1h; OMIM:608104). Autosomal recessive CDG-1h has been curated separately. The preferred disease name suggested for this disorder is autosomal dominant polycystic kidney and/or liver disease - ALG8 (ADPKLD - ALG8).

ALG8 was first reported in relation to ADPLD in 2017 (Besse et al., PMID: 28375157) and in relation to an ADPKD-like phenotype in 2023 (Apple et al. PMID: 36574950). Evidence by Apple et al. 2023 (PMID 36574950) showed that individuals carrying heterozygous ALG8 protein truncating variants (PTV) were at a significantly increased risk of mild cystic kidney disease phenotypes. Jawaid et al 2025 (PMID: 39899384) detected ALG8 variants in 51 families with cystic kidneys and/or livers and illustrated the segregation of 5 different PTV variants with cystic phenotypes in 7 families. In addition, population cohorts with sequence data (Genomics England 100K Genomics Project, UK Biobank, and Mayo Clinic Biobank [MCBB]) showed an enrichment of ALG8 variants in cystic kidney populations, identified by ICD codes. ALG8 variants have incomplete penetrance and a spectrum of clinical presentations from normal kidney structure and function to multiple kidney cysts with CKD. The typical presentation is of limited kidney cysts with preserved kidney function. However, it can also be of severe PLD with limited kidney involvement (ADPLD).

9 variants (4 nonsense, 2 frameshift, 2 canonical splice, and 1 missense) that have been reported in four publications are included in this re-curation (PMIDs: 39899384, 28375157; 32457805; 36574950). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data, case-control data, and segregation data. This gene-disease relationship is also supported by in vitro functional assays showing reduced maturation of polycystin 1 in ALG8 -/- mouse kidney epithelial cells (PMID: 28375157). A total of 1.0/6.0 pts. for experimental evidence was reached.

This gene-disease pair was originally evaluated by the Kidney Cystic and Ciliopathy Disorders GCEP on 07/08/2020 (SOP version 7). It was re-evaluated on 03/10/2025 (SOP version 11). As a result of this reevaluation, the classification increased from Limited to Definitive.

In summary, there is definitive evidence supporting the relationship between ALG8 and ADPKD and ADPLD. This has been repeatedly demonstrated in the diagnostic setting and has been upheld over time. However, many individuals harboring ALG8 PTV do not have any reported cystic phenotypes, suggesting that ALG8 truncating variants may be of low penetrance.