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Published on: June 18, 2018
Novel VAC14 variants identified in two Chinese siblings with childhood-onset striatonigral degeneration
Shuang Liao1,2, Tingting Chen1,2,3, Ying Dai2,4
1Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China.
Insights
Novel variants in the VAC14 gene were identified in two siblings with childhood-onset striatonigral degeneration (SNDC). This expands the known spectrum of VAC14 gene mutations and associated phenotypes in SNDC patients.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Childhood-onset striatonigral degeneration (SNDC) is a neurological disorder.
- The VAC14 gene plays a crucial role in regulating phosphatidylinositol 3,5-bisphosphate levels.
- Pathogenic variants in VAC14 are linked to SNDC and neuronal vacuolation.
Observation:
- Two siblings presenting with SNDC were identified for genetic analysis.
- Whole-exome sequencing was employed to identify the genetic cause.
- The siblings were found to be compound heterozygotes for two novel VAC14 variants.
Findings:
- The identified novel variants (p.Ala582Thr and p.Arg681His) were predicted as likely pathogenic through bioinformatic and modeling studies.
- These variants expand the known spectrum of VAC14 mutations associated with SNDC.
- The affected siblings presented with severe, lethal phenotypes, consistent with most reported SNDC cases.
Implications:
- This study reports the first Asian cases of SNDC caused by VAC14 mutations.
- The findings suggest that VAC14 pathogenic variants may be associated with a broader range of phenotypes than previously understood.
- This research contributes to a more comprehensive understanding of the genetic basis and clinical variability of SNDC.
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.
