ALG11 was first reported in relation to autosomal recessive ALG11-CDG by Rind et al. in 2010 (PMID:20080937). At least 14 unique variants (missense and nonsense) 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 14 probands from 7 publications (PMIDs:20080937, 22213132, 28649519, 28122681, 30676690, 35907674, 36843332). Patient symptoms include failure to thrive, developmental delay, hepatopathy, hypotonia/neurologic abnormalities, hypoglycemia, protein-losing enteropathy, eye abnormalities, immunologic findings, skin abnormalities, a type 1 asialotransferrin profile, and skeletal results. No supporting segregation information is available. 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 ALG11, which is a mannosyltransferase that uses GDP-mannose to sequentially add the fourth and fifth mannose residues to growing dolichol-linked oligosaccharide side chains at the outer leaflet of the endoplasmic reticulum (ER) (PMID: 20080937). Functional alteration of non-patient cells also shows that mutations in the ALG11 gene resulted in variable degrees of impairment in Alg11 activity and N-linked glycosylation (PMID: 16878994). Finally, rescue in patient cells shows that the expression of the wild-type ALG11 cDNA in the respective patient-derived fibroblasts overcomes the accumulations of the shortened oligosaccharides Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol (PMID: 22213132). In summary, there is moderate 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 moderate was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 06/21/2023 (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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