Novel Biallelic Synonymous Exonic Variant in VPS13A Affecting mRNA Splicing: Case Report.

Area of Science:

• Genetics
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Chorea-acanthocytosis (ChAc) is a rare, autosomal recessive disorder.
• It is primarily caused by loss-of-function mutations in the VPS13A gene.
• Understanding the full spectrum of VPS13A variants is crucial for diagnosis and research.

Purpose of the Study:

• To identify the genetic cause of Chorea-acanthocytosis in a patient with specific neurological symptoms.
• To investigate the functional impact of a novel synonymous variant in the VPS13A gene.
• To reclassify the significance of the identified VPS13A variant.

Main Methods:

• Targeted gene sequencing of the VPS13A gene.
• mRNA splicing analysis to assess transcript integrity.
• Western blot to evaluate chorein/VPS13A protein levels.

Main Results:

• A novel homozygous synonymous variant (c.5157C>T; p.Gly1719=) in VPS13A exon 41 was identified.
• This variant was predicted by SpliceAI to cause aberrant splicing.
• RNA analysis confirmed a type III splice variant leading to a frameshift and premature termination codon, with absent chorein protein.

Conclusions:

• The identified synonymous VPS13A variant is reclassified as likely pathogenic.
• This is the first report of Chorea-acanthocytosis caused by a synonymous variant affecting mRNA splicing.
• This case broadens the known spectrum of genetic variants associated with ChAc.