To date a range of different pathogenic variants in the THOC2 gene have been described. These include missense variants that affect the stability of the protein within the cell, as well as splice-site variants that affect the length of the THOC2 protein.
The underlying pathophysiology of THOC2-related disorder is still being researched. THOC2 protein is responsible for a fundamental process of export of molecules (responsible for protein synthesis) from the cytoplasm to the nucleus of each cell. Affected individuals with pathogenic variants in THOC2 most likely have perturbed export of these molecules which results in inappropriate synthesis of (specific or all) proteins, consequently leading to clinical presentations. A range of model systems are being used to elucidate the pathways that are altered in presence of pathogenic variants in THOC2, with a view to explore therapeutic strategies in the future.
Testing for a THOC2-related condition requires sequencing of the THOC2 gene either by traditional sanger sequencing or a next generation sequencing methodology (panel testing, exome or genome). As most THOC2 variants to date are non-recurrent (private to that family) and spread over the gene more work may be required (for example testing of additional family members to segregate the disease, use of in silico tools to predict pathogenicity or molecular/functional studies) to build evidence that a detected variant is causal of the individual’s condition. Repository of the variant and levels of evidence for causality in publically available international database is recommended in order to aid interpretation of novel variants.