ALG1 was first reported in relation to autosomal recessive ALG1-congenital disorder of glycosylation (also known as congenital disorder of glycosylation type 1k) in 2004 (Grubenmann et al., PMID: 14709599). Common phenotypes in affected individuals include severe developmental delay, intellectual disability, microcephaly, hypotonia, early-onset epilepsy, and facial dysmorphism. Additional variable features include coagulation defects, immunodeficiency, and nephrotic syndrome. The most severely affected patients die during the first years of life. Eleven homozygous and compound heterozygous variants (8 missense, including 3 recurrent; 2 splice, 1 nonsense) that have been reported in 10 probands in eight publications (PMIDs: 14709599, 14973782, 20679665, 22966035, 24157261, 26931382, 27325525, 35221878) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by the biochemical function of ALG1, which encodes a protein involved in N-linked glycosylation. Multiple members of the asparagine-linked glycosylation (ALG) family of glycosyltransferases have been implicated in congenital disorders of glycosylation (PMID: 37858231).
In summary, there is definitive evidence supporting the relationship between ALG1 and autosomal recessive ALG1-congenital disorder of glycosylation. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 7, 2024 (SOP Version 10).
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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