Characterization of Two Deep Intronic Variants on the β-Globin Gene with Inconsistent Interpretations of Clinical Significance

Abstract

Sequence variants located in the introns of the β-globin gene may affect the mRNA processing and cause β-thalassemia (β-thal). Sequence variants that change one of the invariant dinucleotides at the exon-intron boundaries may have fatal consequences for normal mRNA splicing. Intronic variants located far from obvious regulatory sequences can be more difficult to evaluate. There is a potential for misinterpretation of such sequence variants. Hence, thorough evaluation of patient data together with critical use of databases and in silico prediction tools are important. Here, we describe two rare sequence variants in the second intron of the β-globin gene, HBB: c.316-70C>G and HBB: c.316-125A>G (NM_000518.4), both previously reported as variants causing β-thal, and later as benign sequence variants. Due to the limited number of published cases and inconsistent interpretations, the significance of these sequence variants has been unclear. We have identified these two sequence variants in multiple individuals, alone and in a variety of combinations with other δ- and β-globin defects, and we find no influence of the sequence variants on the phenotype.

Keywords:

• β-Globin gene
• β-thalassemia (β-thal)
• deep intronic variants
• interpretations
• sequence variants

Acknowledgments

The authors want to thank the engineers Jeanet ter Huurne, Sharda Bisoen, Greet Bakker-Verweij and Rianne Schaap at the Department of Clinical Genetics/LDGA, Leiden University Medical Center, Leiden, The Netherlands, and the biomedical laboratory scientists at the Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway, for outstanding technical assistance.

Disclosure statement

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