Submission Details

The ALG9 gene is located 11q23.1 and encodes an alpha-1,2-mannosyltransferase. The enzyme is involved in N-linked glycosylation and catalyzes two mannose transfers onto lipid-linked oligosaccharide (PMID: 25966638).

Monoallelic ALG9 pathogenic variants were first reported in relation to autosomal dominant polycystic kidney disease (ADPKD) in 2019 (Besse et al., PMID: 31395617). Of note, biallelic ALG9 pathogenic variants have been associated with the congenital disorder of glycosylation, type 1L (CDG-1L; OMIM #6087776) and Gillessen-Kaesbach-Nishimura syndrome (GIKANIS; OMIM #263210). Given that ALG9-associated ADPKD and ALG9-associated CDG-1L have different inheritance modes and phenotypic manifestations, we have split the two disease entities. Here, we only curate the association between ALG9 and ADPKD (http://purl.obolibrary.org/obo/MONDO_0700000). ADPKD-ALG9 patients are characterized by the presence of renal cysts, however, these patients show variable penetrance and expressivity. For instance, Besse et al., 2019 demonstrate that 7/14 of the probands with available abdominal imaging had clear evidence of multicystic kidney disease (multiple kidney cysts, bilaterally), whereas the remaining 7 probands had less than 4 renal cysts (n=4), no imaging data for analysis (n=3), or had reached ESRD by the time of renal imaging (n=1). This large variation of expressivity should be considered when evaluating ALG9 carriers.

At least ten variants (4 nonsense, 3 frameshift, 1 canonical splice-site, and 2 missense) reported in 2 publications have been included in this curation (PMID: 31395617; 37761895). The presumed mechanism of pathogenicity based on published evidence is loss of function whereby variants in the ALG9 gene leads to impaired polycystin-1 maturation (PMID: 31395617). Evidence supporting this gene-disease relationship includes case-level genetic data. Variants in this gene have been reported in at least 19 individuals in 4 publications (PMID: 31395617; 32398770; 37761895; 36573973). Of these individuals, ten were reported to have clear evidence of cystic kidney disease; of the remaining nine, five were reported to not display multiple kidney cysts, three had insufficient clinical data available for assessment, and one harbored a benign variant. This is evidence consistent ADPKD-ALG9 having variable penetrance and expressivity. For this gene-disease curation, only the ten probands who showed clear evidence of cystic kidney disease as well as putatively pathogenic ALG9 variants were counted for case-level genetic evidence. A total of 12 pts. for genetic evidence was reached.

In summary, there is “Definitive” evidence to support this gene-disease relationship and no convincing evidence has emerged that contradicts the relationship. This gene-disease pair was originally evaluated as ”Moderate” by the Kidney Cystic and Ciliopathy Disorders GCEP on 08/26/2020 (SOP Version 7). It was reevaluated on 09/11/2023 and the classification changed (SOP Version 9).