Novel VAC14 variants identified in two Chinese siblings with childhood‐onset striatonigral degeneration

BACKGROUND: VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5‐bisphosphate [PI (3,5) P2]. VAC14 pathogenic variants cause prominent vacuolation of neurons in basal ganglia of patients with childhood‐onset striatonigral degeneration (SNDC). METHODS: We identified two siblings with SNDC. Whole‐exome sequencing was performed for genetic molecular analysis in these probands. RESULTS: The patients were compound heterozygotes for two novel variants in the VAC14 gene, p.Ala582Thr and p.Arg681His. The pathogenicity of these variants was indicated by a bioinformatic study and protein three‐dimensional modeling. Eight previously reported SNDC cases and a Yunis–Varón syndrome caused by VAC14 mutations were summarized and compared. CONCLUSION: We present novel compound heterozygous variants (c.1744G>A/c.2042G>A) in our proband, and these novel variants were predicted to be likely pathogenic. The affected siblings were clinically severe and lethal; their phenotypes were similar to the majority of previously reported SNDC cases, with the exception of two cases that showed mild clinical manifestations. VAC14 pathogenic variants may be associated with various phenotypes. Herein, we report the Chinese siblings with SNDC, they are the first Asian cases. Our results expanded the spectrum of VAC14 pathogenic variants and the ethnic backgrounds of the affected cases.