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

Objectives: Chorea-acanthocytosis is an autosomal recessively inherited condition caused by loss-of-function pathogenic variants in VPS13A. We identified a novel synonymous exonic variant leading to abnormal mRNA splicing in a patient with chorea-acanthocytosis.

Methods: A patient with focal epilepsy developed generalized chorea with orolingual dystonia, cognitive decline, and peripheral neuropathy, consistent with chorea-acanthocytosis. Her parents were first cousins, but there was otherwise no family history. Targeted gene sequencing for variants in VPS13A, mRNA splicing analysis, and Western blot for chorein were performed.

Results: A homozygous synonymous variant in exon 41 of VPS13A (NM_033305.3): c.5157C>T; p.Gly1719 = was identified; this was previously classified as a variant of uncertain significance. SpliceAI predicted a splice donor gain with a score of 0.75 2 base pairs upstream of the reported variant. RNA splicing analysis revealed the creation of a type III splice variant, resulting in a frameshift and a premature termination codon. Western blot showed absent chorein/VPS13A protein.

Discussion: The variant is reclassified as likely pathogenic based on the American College of Medical Genetics criteria. This is the first reported case of ChAc caused by a synonymous variant in VPS13A proven to affect splicing. Our report further expands the spectrum of variants known to cause ChAc.