DDOST was first reported in relation to autosomal recessive congenital disorder of glycosylation in 2012 (Jones et al., PMID 22305527). At least 7 unique variants (missense, frameshift) have been reported. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 4 probands from 4 publications (PMIDs 22305527, 33413482, 34462534, 36214423). Patients have a range of clinical features, including developmental delay, hypotonia, failure to thrive, eye abnormalities, gastrointestinal involvement, and liver dysfunction. 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 DDOST, which encodes a subunit of the oligosaccharyl transferase complex (OST complex) which plays a key role in N-glycosylation (PMIDs 1600939, 37848450). Rescue experiments in patient fibroblasts demonstrated that wild type DDOST restores glycosylation (PMID 22305527).
In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Disorders of Glycosylation Gene Curation Expert Panel on November 15, 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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