Abstract
ABSTRACT
Background
The BORCS5 is an important and critical component of the BLOC‐one‐related complex (BORC), involved in kinesin‐dependent anterograde lysosomal transport. Aberrations in the octameric protein complex encompass lethal neurological manifestations, such as arthrogryposis multiplex congenita, brain malformations and neuropathological evidence of diffuse neuroaxonal dystrophy. Loss‐of‐function variants in
BORCS5
are associated with extremely rapid and progressive neurodegeneration.
Methods
Herein, we present a family consisting of a proband with intellectual disability, microcephaly, developmental delay, facial dysmorphism, dystonia, focal/generalized seizures and speech delay. We performed whole‐exome sequencing followed by Sanger sequencing for molecular diagnosis. Further, we performed 3D protein modelling for structural interpretation.
Results
Genetic analysis identified a novel stop‐gain variant (NM_058169.6, c.262C>T; NP_477517.1, p.(Gln88*)) in
BORCS5
, subsequently confirmed by Sanger sequencing. The variant is likely pathogenic (PVS1, PM2, PP3). Protein modelling of the BORCS5; p.(Gln88*) variant showed a distinct conformation compared with the wild‐type BORCS5, suggesting a potential role for the unfolded protein response in the pathogenesis of BORCS5.
Conclusion
In summary, our findings exemplify a novel stop‐gain variant in
BORCS5
associated with diverse pathological manifestations, underscoring the importance of further exploring this gene in patients lacking identifiable disease‐causing gene variants.