Vici syndrome was first reported in PMID:3344762 by Vici et al. This condition is characterized by central features of agenesis or thinning of corpus callosum, developmental delay/intellectual disability, comined immunodeficiency with signs of thymic aplasia/hypoplasia, cardiomyopathy, cataracts, and microcephaly. To date approximately 90 individuals have been reported with biallelic variants in EPG5 (Dafsari, Gene reviews 2022). In this curation, 12 variants were scored including frameshift, missense, nonsense, and splice site variants across 7 probands from 4 publications (PMIDs:26395118, 23222957, 26917586, 344762) to reach a maximum score of genetic evidence. Heterozygous parents and siblings were unaffected. The mechanism of pathogenicity is loss of function.
This gene-disease association is also supported by the biochemical function of EPG5 (PMID:27588602).EPG5 is a protein involved in autophagy, which facilitates fusion specificity of autophagosomes with late endosomes and lysosomes. Patient fibroblasts have been shown to have impaired autophagy. Multi-system effects may be due to disrupted autophagy function, which plays a crucial role in cell homeostasis through the recycling/ degredation of protein products/organelles and the role of autophagy pathways in immune system defense. Additionally, the gene-disease relationship is supported by knock out EPG5 (-/-) mice (PMID: 23674064). EPG5 knockout mice recapitulated the phenotypes of pathologic corpus callosum changes and myopathy, including an increase in centrally located nuclei. However, knock out EPG5 mice grew to be sexually active adults and failed to recapitulate phenotypes such as facial dysmorphia, hypopigmentation, immunodeficiency phenotypes cataracts, and cardiac changes. Finally, the gene-disease relationship is supported by knock out EPG5 zebrafish (PMID: 30806141). EPG5 (-/-) zebrafish displayed phenotypes such as cardiomyopathy, growth impairment, and perhaps most notably, defective autophagy pathway and features of myopathy. In summary, there is definitive evidence to support this gene-disease relationship.
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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