Cornejo, Patricia

Abstract 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.

Background Super‐resolution is a promising technique to create isotropic image volumes from stacks of two‐dimensional (2D) motion‐corrupted images in fetal magnetic resonance imaging (MRI). Purpose To determine an acquisition quality metric and correlate that metric with radiologist perception of three‐dimensional (3D) image quality. Study Type Retrospective. Subjects Eighty‐seven patients, mean gestational age 29 ± 6 weeks. Field Strength/Sequence 1.5 T/ 2D fast spin‐echo. Assessment Four radiologists (L.G., D.M.E.B., P.C., and J.V.; 31, 21, 7, and 7 years' experience, respectively) graded reconstructions on a 0 to 4 scale for overall appearance and visibility of specific anatomy. During reconstruction, slices were labeled as inliers based on correlation between a simulated vs. actual acquisition. The fraction of brain voxels in inlier slicers vs. total brain voxels was measured for each acquisition. Statistical Tests Paired sample t test, Pearson's correlation, intra‐class correlation. Results The average brain mask inlier fraction for all acquisitions was 0.8. There was a statistically significant correlation (0.71) between overall reconstruction appearance and number of acquisitions with inlier fraction above 0.73. There was low correlation (0.21, P = 0.05) between the number of acquisitions used in the reconstruction and overall score when no data quality measure was considered. Similar results were found for ratings of specific anatomy. Statistically significant differences in overall perception of image quality were found when using three vs. four, four vs. five, and three vs. five high‐quality acquisitions in the reconstruction. Five high‐quality acquisitions were sufficient to yield an average radiologist rating of 3.59 out of 4.0 for overall image quality. Data Conclusion Reconstruction quality can be reliably predicted using the brain mask inlier fraction. Real‐time super‐resolution protocols could exploit this to terminate acquisition when enough high‐quality acquisitions have been collected. To achieve consistent 3D image quality it may be necessary to acquire more than five scans to compensate for severely motion‐corrupted acquisitions. Level of Evidence 3 Technical Efficacy 1