Strides in STXBP1 Research December 2024
2024 was an excellent year for STXBP1 publications with several outstanding papers published. The year ended with two interesting papers.
So, what was new in December 2024?
A group of researchers working with Simons Searchlight published a paper on reevaluating genetic variants in neurodevelopmental disorders (NDDs). Simons Searchlight is a patient registry for people with NDDs, including STXBP1 (many of our families are enrolled in Simons Searchlight – if you haven’t, you should). The paper describes how Simons reevaluates and reinterprets genetic variant information supplied to them by patients, or family members, for individuals with NDDs; especially variants which are classified as variants of uncertain significance (VUS). Variants (or mutations) in a gene come in 5 flavors: benign, likely benign, VUS, likely pathogenic, and pathogenic; depending on how strong the evidence is for a particular variant to cause a disease. Being able to determine if a particular VUS is either benign or pathogenic is very important as certain future precision therapies, like gene therapy, may be limited to individuals with likely pathogenic or pathogenic variants. Simons evaluated 2834 genetic laboratory reports from 91 genetic conditions associated with autism and NDDs between 2013 and 2022. They reclassified about 20.4% of the variants with 230 variants being classified up (more pathogenic) and 173 downgraded (more benign). Of 351 VUSs associated with single-gene disorders like STXBP1, 25.4% were reclassified as likely pathogenic or pathogenic. Interestingly, VUSs in SCN2A, SLC6A1, or STXBP1 were more likely to be reclassified compared to variants in other genes. This underscores the importance of our STXBP1 families taking part in patient registries like Simons Searchlight.
A group of scientists from China published their work on identifying biomarkers for rare autoimmune eye diseases. They found that low levels of STXBP1 protein is associated with a particular eye disease called Vogt-Koyanagi-Harada syndrome, an inflammatory disorder associated with autoimmune reactions against pigmented tissues like the uvea, which is the pigmented, or colored, part of your eye. There is increasing evidence that STXBP1 plays a role in immune response. One such role may be in regulating what is known as granule-mediated cytotoxicity. Certain types of immune cells, cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells kill cancer cells and cells infected with viruses by releasing molecules known as ‘cytotoxic granules’ when the CTLs or NKs are in close proximity to the cancer or infected cell. The process of granule release is very similar to the release of neurotransmitters at the synapse. STXBP1 has been demonstrated to play a role in this granule release, though its role is more complementary than primary. The Chinese researchers speculate that reduced STXBP1 protein may reduce the activity of CTLs and NK cells leading to an increase in ‘abnormal cells’ in the uvea that trigger an immune response. While the evidence for a role of STXBP1 in immune function is increasing, we have no clear evidence that people with STXBP1-RD have any immune function problems.
