Submission Details

DPM3 was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Lefeber DJ et al., 2009 (PMID: 19576565). At least 5 unique variants, all missense, have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental findings. Variants in this gene have been reported in at least 10 probands from publications (PMIDs: 19576565, 28803818, 30931530, 31266720, 31469168, 35932216). Patients exhibit a range of symptoms, including muscle weakness, creatine kinase elevation, cardiomyopathy, developmental delay, microcephaly, and neurological symptoms. Common neurological phenotypes associated with DPM3 mutations include seizures, motor signs such as Babinski and Gowers signs, and other abnormalities like cerebral arteriovenous malformation, abnormal brain morphology, ataxia, dysarthria, and focal-onset seizures with associated motor and sensory deficits. No supporting segregation information is available, and 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 DPM3, which encodes the stabilizer subunit of the dolichol-phosphate mannose (DPM) synthase complex, tethering catalytic subunit DPM1 to the endoplasmic reticulum (PMID: 10835346). Altered expression of DPM3 in patients shows that DPM synthase activity in all patient cells was reduced by more than 70%. Immunoblotting in those same cells revealed a significant reduction in IIH6 labeling, indicating glycosylation problems (PMID: 30931530). In summary, there is strong evidence supporting this gene-disease relationship. Although additional genetic and experimental evidence is needed to establish 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 12/6/23 (SOP Version 10).