TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.

Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Evaluation of Serum Biomarkers and Electroencephalogram to Determine Survival Outcomes in Pediatric Post-Cardiac-Arrest Patients.

Cardiac arrest causes primary and secondary brain injuries. We evaluated the association between neuron-specific enolase (NSE), serum S-100B (S100B), electroencephalogram (EEG) patterns, and post-cardiac arrest outcomes in pediatric patients. A prospective observational study was conducted in the pediatric intensive care unit and included 41 post-cardiac arrest patients who underwent EEG and serum sampling for NSE and S100B. The participants were aged 1 month to 18 years who experienced cardiac arrest and underwent CPR after a sustained return of spontaneous circulation for ≥48 h. Approximately 19.5% (n = 8) of patients survived until ICU discharge. Convulsions and sepsis were significantly associated with higher mortality (relative risk: 1.33 [95% CI = 1.09-1.6] and 1.99 [95% CI = 0.8-4.7], respectively). Serum NSE and S100B levels were not statistically associated with the outcome (p = 0.278 and 0.693, respectively). NSE levels were positively correlated with the duration of CPR. EEG patterns were significantly associated with the outcome (p = 0.01). Non-epileptogenic EEG activity was associated with the highest survival rate. Post-cardiac arrest syndrome is a serious condition with a high mortality rate. Management of sepsis and convulsions affects prognosis. We believe that NSE and S100B may have no benefit in survival evaluation. EEG can be considered for post-cardiac arrest patients.