Childhood onset hereditary spastic paraplegia

Gene: TBCB

I don't know

Comment on list classification: Rating Amber following consultation with the Genomics England Clinical Team. Some functional data that indicates disruption of the gene, however this does not provide conclusive support for pathogenicity of the founder variant. Additional functional evidence or corroborative cases would allow verification of this gene-disease association and future review of the classification on this panel.

Created: 13 Oct 2025, 2:13 p.m. | Last Modified: 13 Oct 2025, 2:13 p.m.

Panel Version: 8.16

PMID: 40856104 (2025) - 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with the same homozygous founder variant (c.589T>A, p.(Tyr197Asn)) in TBCB. Affected individuals presented during infancy with motor or speech delays and developed late-childhood-onset spastic paraparesis (onset around 9-12 years old), global developmental delay (formal assessment done in 5 individuals, indicating mild ID), and autism spectrum. Brain MRI showed corpus collosum thinning in 3, and decreased white matter in 2.

The c.589T>A (GRCh38: 19-36125492-T-A) variant has an AF of 0.006485 in the Ashkenazi Jewish population in gnomAD v4 with 0 homozygotes. Classified as VUS in ClinVar based on 1 submission.

TBCB protein levels were reduced in patient fibroblasts. Drosophila melanogaster model showed reduced survival and impaired climbing ability.
Sources: Literature

Created: 3 Oct 2025, 1:01 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder, MONDO:0700092

Publications

• 40856104