Submission Details

EDEM3 was first reported in relation to autosomal recessive Congenital Disorder of Glycosylation, Type 2v [CDG2v] (MONDO:0030423) in 2021 (Polla DL et al. 2021; PMID:34143952). CDG2v is a rare autosomal recessive disorder characterized by neurodevelopmental delay and variable facial dysmorphisms. Result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The disease can be caused by homozygous or compound heterozygous mutation in the EDEM3 gene (610214) on chromosome 1q25. EDEM3 is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. It is a rare, multisystemic, inherited condition caused by an abnormal protein which cannot effectively target misfolded glycoproteins. ER (Endoplasmic Reticulum) quality control is an elaborate mechanism conserved from yeast to mammals, ensuring that newly synthesized proteins in the ER fold and assemble correctly and that only proteins that acquire their correct conformations are sorted further into the secretory pathway. During this process, proteins that fail to attain their native conformation due to mutations of the polypeptides or to ER stress conditions adverse for protein folding as well as orphan subunits are degraded in a process known as ER-associated degradation (ERAD)

More than 70 unique variants (e.g., synonymous, missense, in-frame indel, nonsense, frameshift) have been reported in humans by ClinVar. Evidence supporting this gene-disease relationship includes case-level data and experimental data. 4 variants (1 nonsense, and 3frameshift) that have been reported in approximately 4 probands in 1 publication (Polla DL et al. 2021; PMID:34143952), are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by protein interaction, expression, and animal models studies (Hosokawa N et al., 2001; PMID: 11375934; Yu S et al. 2018; PMID:29784879; Polla DL et al. 2021; PMID:34143952). In summary, there is strong evidence to support the relationship between EDEM3 and Congenital Disorder of Glycosylation, Type 2v. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date February 7, 2024 (SOP Version 10).