The first report of heterozygous pathogenic variants in ALG6 causing autosomal dominant polycystic kidney disease (ADPKD) was in 2020 (Schonauer et al., PMID: 32398770) followed by another study in 2023 (PMID: 36807342). Biallelic variants in ALG6 variants have been definitively demonstrated to cause congenital disorder of glycosylation, type Ic (CDG-1c; OMIM #603147). However, cystic kidney disease has not been reported as a part of the phenotypic spectrum of this condition thus far. Given the different inheritance modes and phenotypes associated with ALG6-related ADPKD and ALG6-related CDG-1c, we have split the two disease entities. As noted above, this curation is related to the association between ALG6 and ADPKD. So far, 6 variants (4 loss of function and 2 missense) have been reported in literature, to be associated with ADPKD, of which the 2 missense variants are reported as variants of uncertain significance (VUS) and 3 out 4 loss of function variants are reported as Likely Pathogenic (LP) or Pathogenic (P) in ClinVar; but in relation to the autosomal recessive congenital disorder of glycosylation condition. Patients with ADPKD phenotypes reported in these studies are also reported to occasionally present with polycystic liver disease (PMIDs: 32398770, 36807342). Evidence supporting this gene-disease relationship includes case-level data for all variants and additional experimental data for a recurrent variant. No other functional studies demonstrating the role of ALG6 in renal function or cyst formation have been published so far. Though no evidence currently contradicts this gene-disease relationship, more evidence is required to demonstrate an unequivocal causal role for ALG6 in cystic kidney disease. However, there are many individuals in the general population harboring variants ALG6 (including those reported as disease-causing in the two publications and LP/P variants in ClinVar) that do not have any reported cystic phenotype, indicating that truncating variants in ALG6 may either be risk alleles for polycystic kidney phenotypes, or this gene-disease relationship may have low penetrance. In summary, there is currently Limited evidence to support this gene-disease relationship. This gene-disease pair was evaluated as limited and approved by the Kidney Cystic and Ciliopathy Disorders GCEP on 10/25/2023 in accordance with SOP Version 9.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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