Identification of a Novel TBCK Variation in an Azari Consanguineous Family With Psychomotor Developmental Disorder

TBC1 domain-containing kinase (TBCK; MIM #616900) is implicated in autosomal recessive neurodevelopmental disorders with hypotonia and developmental delay. TBCK regulates mTOR signaling, lysosomal activity, and intracellular trafficking, but the full spectrum of pathogenic variants remains poorly understood. We investigated a consanguineous Iranian family with psychomotor delay. Whole exome sequencing (WES) identified a candidate TBCK variant, confirmed by Sanger sequencing. Functional studies were performed using amniotic fluid-derived cell culture, Western blotting, protein structural modeling, and molecular docking analyses. A novel homozygous frameshift variant, TBCK (NM_001163435.3): c.1969dupT (p.Cys657Leufs*17), was detected and absent from population databases. Clinically, the proband presented with severe developmental delay, hypotonia, seizures, and facial dysmorphism, and died at 9 months. Western blotting showed a significant decrease in TBCK expression (p < 0.007). Structural analysis of a theoretically modeled truncated protein indicated C-terminal truncation with loss of critical domains, while in silico docking demonstrated reduced binding affinity between mutant TBCK and Rab1B, suggesting impaired Rab-mediated trafficking. This study reports a novel pathogenic TBCK variant associated with severe neurodevelopmental delay, contributing to the clinical and molecular spectrum of TBCK syndrome. Our findings underscore the importance of genetic testing in rare neurodevelopmental disorders and provide insight into the molecular mechanisms underlying TBCK dysfunction.