Bi-allelic loss-of-function variants in BCAS3 cause a syndromic neurodevelopmental disorder

Area of Science:

• Genetics
• Neuroscience
• Cell Biology

Background:

• BCAS3 (microtubule-associated cell migration factor) is a conserved cytoskeletal protein.
• Previous research suggested roles in angiogenesis, embryogenesis, and tumorigenesis.

Observation:

• Germline bi-allelic loss-of-function variants in BCAS3 were identified in 15 individuals across eight families.
• Probands presented with global developmental delay, pyramidal tract involvement, microcephaly, short stature, strabismus, dysmorphic features, and seizures.

Findings:

• Absence of BCAS3 protein confirmed loss-of-function in probands' fibroblasts.
• Transcriptomic and proteomic analyses revealed dysregulated pathways in human fibroblasts and a Bcas3 knockout mouse model.
• A Drosophila model further supported BCAS3's crucial role in neural tissue development.

Implications:

• BCAS3 variants are causative for a novel neurodevelopmental disorder.
• The findings highlight BCAS3's essential function in human neural development, distinct from its previously proposed angiogenic roles.
• This study expands the understanding of genetic factors contributing to neurodevelopmental disorders.