A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

Researchers found a genetic change in the TBCB gene that causes a rare condition affecting 10 people, mostly from Ashkenazi Jewish families. Children with this genetic change develop walking difficulties, developmental delays, and autism features in late childhood. The genetic change reduces important protein levels needed for brain and nerve development.

This genetic study identified a founder variant in the TBCB gene causing a new form of hereditary spastic paraparesis in 10 individuals, primarily from Ashkenazi Jewish backgrounds. The homozygous c.589T>A variant leads to reduced TBCB protein levels and causes a complex neurodevelopmental disorder characterized by late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum features. Functional studies in yeast and fruit fly models confirmed the variant's pathogenic effects on cellular function and survival. The research establishes TBCB as essential for central nervous system development and axonal function, representing a novel genetic cause of combined movement disorder and neurodevelopmental conditions.

Establishes TBCB variants as a cause of complex neurodevelopmental disorder. Requires genetic counseling for at-risk populations. Multidisciplinary management needed for spasticity, developmental delays, and autism features. May inform future targeted therapies for microtubule-related disorders.

Small cohort of 10 individuals limits generalizability. Study type not specified. Long-term outcomes and treatment responses not assessed. Functional studies conducted in non-human models may not fully reflect human pathophysiology.

Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB.

Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum.

TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population.

Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.