Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders
Tipu Sultan1, Giovanna Scorrano2, Marta Panciroli3
1Department of Pediatric Neurology, Children Hospital Lahore, Main Boulevard Gulberg, Nishtar Town, Lahore, Punjab 54000, Pakistan.
Insights
Researchers identified a novel VPS13D gene variant causing severe neurodevelopmental impairment and hyperkinetic movements in a Pakistani family. This finding expands understanding of VPS13D-related disorders and their varied clinical presentations.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Cell Biology
Background:
- The VPS13 protein family is crucial for lipid transport and maintaining organelle membrane homeostasis.
- Pathogenic variants in VPS13 genes are linked to human neurodevelopmental and neurodegenerative disorders.
- VPS13D specifically plays a role in mitochondrial homeostasis and function.
Purpose of the Study:
- To investigate the genetic cause of neurodevelopmental impairment and hyperkinetic movements in a Pakistani family.
- To delineate the clinical spectrum of VPS13D-related neurological disorders.
Main Methods:
- Whole exome sequencing (WES) and Sanger sequencing were employed to identify causative variants.
- Clinical phenotypes and natural history were documented over a 3-year follow-up.
- Literature data on previously identified VPS13D-related neurological disorders were summarized.
Main Results:
- A homozygous non-synonymous variant (c.5723 T > C; p.Ile1908Thr) in the VPS13D gene was identified as the likely cause.
- Affected siblings presented with early-onset global developmental delay, speech and motor impairments, and hyperkinetic movement disorders.
- Neurological abnormalities were observed, some progressive and some non-progressive.
Conclusions:
- A novel VPS13D homozygous variant associated with severe neurological impairment was described.
- The study highlights the heterogeneity of VPS13D-related clinical phenotypes.
- Further research is needed to understand VPS13D function, its impact on mitochondria and brain development, and to establish genotype-phenotype correlations for prognosis and potential therapies.
Background:
The VPS13 family of proteins has been implicated in lipid transport and trafficking between endoplasmic reticulum and organelles, to maintain homeostasis of subcellular membranes. Recently, pathogenic variants in each human VPS13S gene, have been linked to distinct human neurodevelopmental or neurodegenerative disorders. Within the VPS13 family of genes, VPS13D is known to be implicated in mitochondria homeostasis and function.
Methods:
We investigated a Pakistani sibship affected with neurodevelopmental impairment and severe hyperkinetic (choreoathetoid) movements. Whole exome sequencing (WES) and Sanger sequencing were performed to identify potential candidate variants segregating in the family. We described clinical phenotypes and natural history of the disease during a 3-year clinical follow-up and summarized literature data related to previously identified patients with VPS13D-related neurological disorders.
Results:
We identified by WES an homozygous non-synonymous variant in VPS13D (c.5723 T > C; p.Ile1908Thr) as the potential underlying cause of the disease in our family. Two young siblings developed an early-onset neurological impairment characterized by global developmental delay, with impaired speech and motor milestones, associated to hyperkinetic movement disorders as well as progressive and non-progressive neurological abnormalities.
Conclusion:
In this study we delineated the heterogeneity of VPS13D-related clinical phenotypes and described a novel VPS13D homozygous variant associated with severe neurological impairment. Further studies will be pivotal to understand the exact VPS13D function and its impact on mitochondria homeostasis, brain development and regulation of movements, to further clarify genotype-phenotype correlations and provide crucial prognostic information and potential therapeutic implications.
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