A novel cryptic splice donor due to synonymous variant in as an underlying cause of a chorea-acanthocytosis in a large family.

Chorea-acanthocytosis (ChAc) is a rare inherited disease of the nervous system. In this disease the neurological manifestations are associated with acanthocytosis of the red blood cells. The clinical features appear in the third to fourth decades of life. Generalized weakness, choreiform movement disorder, decline in cognition, and psychiatric symptoms are the characteristic features of the disease. The differential diagnosis between Huntington's disease and ChAc is difficult because both the diseases share similar neurological features. Herein, we recruited a large family with multiple individuals initially diagnosed as having Huntington's disease. Analysis of the DNA samples of affected individuals by exome sequencing detected a synonymous variant (NM_001018037.2; c.5040C > T) in the . Multiple splice site detection tools were used to predict the potential pathogenicity of the novel synonymous variant. The variant, identified in this study, was predicted to be a cryptic splice donor site that may lead to aberrant pre-mRNA splicing. Reverse transcriptase PCR analyses of patient blood-derived RNA showed activation of a cryptic mid-exon splice donor, leading to frameshift. The variant was confirmed in all other affected and unaffected individuals using Sanger sequencing. This is the first report of synonymous variants of as an underlying cause of ChAc. Our results provide the first direct evidence of the involvement of a synonymous variant of in ChAc. Additionally, this study emphasized the importance of considering gene mutations in the screening of Huntington's patients.