A Novel BORCS5 Loss‐Of‐Function Variant in a Patient With a Rare Neurodevelopmental Disorder

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.