Submission Details

DPM1 was first reported in relation to autosomal recessive Congenital Disorders of Glycosylation by Imbach T, et al., 2000, (PMID: 10642602). At least 9 unique variants (such as missense, frameshift, or deletions) 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 10 probands from publications (PMIDs:15669674, 10642602, 10642597, 27481510, 16641202, 23856421, 30653653 and 35910228). Patients have a range of symptoms, including severe developmental delay, microcephaly, seizures, ataxia, peripheral neuropathy, eye abnormalities (retinopathy, nystagmus, strabismus), and severe gastrointestinal involvement. 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 DPM1, which encodes the cytoplasmic catalytic subunit of dolichol-phosphate-mannose synthase, an enzyme complex that synthesizes dolichol-phosphate-mannose (Dol-P-Man) from GDP-mannose and dolichol-phosphate (PMID: 10835346). DPM1 knockdown in a zebrafish model displayed features of congenital disorder of glycosylation type 1e (CDG1e) associated with DPM1 mutations, such as microcephaly, smaller eyes, kinked tail, and occasional vascular defects in the tail vein. In that same model, rescue of the phenotype was done and was restored. In summary, there is definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. A classification of DEFINITIVE was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 10/4/23 (SOP Version 9).