ALG2 was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Thiel C, et al., 2003 (PMID: 12684507). At least 6 unique variants (varied in missense,frameshift, indels) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 5 probands from publications (PMIDs: 12684507, 34980536, 23404334, 30397276, 33644825). Patient have a range of range of symptoms, such as developmental delay, seizures, poor vision, coagulopathy, and delayed myelinization. Patients may also present with congenital myasthenic syndromes (CMS) which characterized by fatigable muscle weakness. The disease mechanism appears to be biallelic loss of function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of ALG2, which encodes an alpha-1,3-mannosyltransferase that catalyzes the second and third mannosylation steps in the N-linked glycosylation pathway (PMID: 23404334). A yeast assay was done where cDNAs encoding wild type hALG2 or the Δ1040G mutant were introduced into the temperature-sensitive alg2-1 yeast strain.This showed that only the wild-type hALG2 cDNA, not the mutant Δ1040G form, restored the formation of lipid-linked oligosaccharides in alg2-1 cells (PMID: 12684507) In addition, an *ALG2 *mutant medaka model was employed to explore the effects of *ALG2 *gene mutations on embryonic development. The investigation revealed that introduced mutations in the ALG2 gene resulted in abnormalities during late-stage embryonic development, reminiscent of the multisystemic phenotypes observed in ALG2-CDG patients. In that same model there was rescue of the phenotype with the injection of either medaka or human alg2 mRNA, the survival of homozygous mutant embryos was restored (PMID: 34106226). In summary, there is strong evidence to support this gene-disease relationship. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of STRONG was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 11/15/23 (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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