Novel α-Globin Splice Site Mutation (HBA2: c.96-5C>A) in Combination with Three-Gene Deletion Hb H Disease

Abstract

The choice of acceptor splice site during exon-exon splicing by the spliceosome is determined by a variety of factors. We report here a family with a novel acceptor splice site variant within intron 1 of the α-globin gene that provides some in vivo insight into the rules governing RNA splicing in homo sapiens. A 2-year-old female with Hb H disease, was found to have not only three α-globin genes deleted (– –^FIL/–α^3.7) but also a HBA2: c.96-5C>A variant on her remaining α-globin gene. The HBA2: c.96-5C>A variant was in cis with –α^3.7 and mRNA studies indicate that this variant creates a new acceptor splice site which is used in approximately 35.0% of α-globin mRNA transcripts. The reduced levels of normal mRNA transcript predicts a more severe Hb H disease than expected for the three-gene deletion Hb H disease with a phenotype similar to nondeletional Hb H disease. We propose that this variant be called Hb Beach Haven (HBA2: c.96-5C>A).

KEYWORDS:

• Acceptor splice site
• α-globin gene
• Hb H disease
• mutation
• RNA splicing

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.