The TRAPPC4 gene is located on Chromosome 11. It is known that TRAPPC4 is essential for life, as complete knockout of the gene is embryonic lethal in mice. The sequence variants identified in the TRAPPC4 gene (NM_016146.6) are:
Homozygous splicing variant c.454+3A>G
• Affected individuals are homozygous for the variant, and heterozygous carriers appear unaffected.
• The majority (>90%) of affected individuals have the same homozygous TRAPPC4 variant NM_016146.6(TRAPPC4):c.454+3A>G
• This variant is relatively common in the population, shown by the relatively high frequency in population databases. It is speculated that this location is a ‘pathogenic variant hotspot’ because there is lack of evidence of a common ‘ancestral’ origin.
• This variant is located at a well-conserved splice site in the TRAPPC4 gene, resulting in a leaky splicing effect
• The majority of TRAPPC4 transcript produced contains mis-splicing events, with reduced expression of wild-type transcript.
• There are low levels of wild-type TRAPPC4 transcript, which results in some TRAPPC4 protein expressed and partial TRAPP complex assembly defects.
Homozygous missense variant c.191T>C (p.Leu64Pro)
• In silico analyses of the p.(Leu64Pro) variant predicted destabilisation of the core structure of the protein and decreased protein stability.
• This variant is not common.
• A child presented with an early infantile neurodevelopmental phenotype consistent with previous reports of TRAPPC4-associated disorders
Homozygous missense variant c.278C>T (p.Pro93Leu)
• The p.(Pro93Leu) was predicted to alter a residue on the surface of TRAPPC4 that may destabilise internal protein interactions, altering spatial conformation of the protein.
• This variant is not common.
• Two siblings homozygous for the c.278C>T variant presented with cognitive delay in early childhood, late-onset regression of achieved milestones, and microcephaly.