Identification and functional analysis of a novel TBC1D23 pathogenic variant in a Chinese family with pontocerebellar hypoplasia

Our study identifies c.511_512delTT as a novel pathogenic variant in TBC1D23. We propose the severe phenotype stems from a primary loss-of-function (LoF), which is likely exacerbated by the cytotoxic effect of the truncated protein produced via partial NMD escape. Our findings suggest this mutant protein exhibits increased stability. This model provides a novel explanation for the phenotypic heterogeneity in PCH11 and expands the mutational spectrum of this disorder.