The TRAPPC4 gene is located on chromosome 11 at 11q23.3 and encodes a highly conserved component of the TRAPP (TRAfficking Protein Particle) complex, which regulates key intracellular vesicular trafficking events, including secretion, and is involved in autophagy. TRAPPC4 was first reported in relation to autosomal recessive neurodevelopmental disorder with epilepsy, spasticity, and brain atrophy (NEDESBA) in 2020 (Van Bergen et al., PMID: 31794024). NEDESBA has features of severe global developmental delay evident in infancy, with early-onset seizures, and hypotonia. Some individuals may present with hearing loss and vision issues. The condition is mainly caused by a splicing variant; eight affected probands from eight families with this variant are included in this curation (PMIDs: 31794024, 32901138). Two missense variants more recently found in three probands in two affected families are also included in this curation (PMID: 34878169). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence including rescue, interaction, and functional alteration evidence (PMIDs: 20972447, 31794024). The splicing variant was shown to inhibit autophagy through a functional alteration study in patient fibroblasts, and function in patient fibroblasts cells could be rescued by introducing TRAPPC4. In addition, a study in yeast demonstrated that the protein is essential for a TRAPP complex, which contains nine subunits and is associated with intellectual disability. In summary, there is definitive evidence supporting the relationship between TRAPPC4 and autosomal recessive NEDESBA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 12/6/23 (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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