A Family with γ-Thalassemia and High Hb A₂ Levels

Abstract

We describe a family carrying a γ-globin gene deletion associated with an increase of Hb A₂ level beyond the normal range. The family included the proband, his sister and their father, all with increased Hb A₂ and normal Hb F levels. The proband and his sister showed borderline values of mean corpuscular volume (MCV) and reduced values of mean corpuscular hemoglobin (Hb) (MCH). The proband was referred to our Medical Genetics Service for preconception counseling together with his partner, a typical β-thalassemia (β-thal) carrier. The results were negative for the most frequent α-thalassemia (α-thal) mutations, and had no significant sequence variations of the coding sequences and promoter of the β- and δ-globin genes. Quantitative analysis by multiplex ligation-dependent probe amplification (MPLA) of the β-globin gene cluster detected a heterozygous deletion, ranging between 2.1 and 4.7 kb, in the proband, his sister and the father. The deletion involved the ^Gγ gene and ^Gγ-^Aγ intergenic region, whereas the 3' region of the ^Aγ gene was preserved. A subsequent gap-polymerase chain reaction (gap-PCR) showed that a hybrid ^GAγ fusion gene was present. The deletion segregated with the elevation of Hb A₂. The MLPA analysis of the β-globin gene cluster in 150 control alleles excluded a common polymorphism. Despite stronger evidence being needed, the described family suggests a possible role of this γ-globin gene deletion in contributing to Hb A₂ elevation, possibly by altering the transcription regulation of the cluster. We propose γ-globin gene dosage analysis to be performed in patients with unexplained elevated Hb A₂ levels.

• γ-Thalassemia (γ-thal)
• genetic counseling
• globin gene deletion
• high Hb A₂ level

Acknowledgments

We wish to acknowledge the proband and his family for participating in this study. We are grateful to Dr. Marco Lucci (Dipartimento di Riproduzione e Accressimento e Dipartimento di Scienze Mediche, Unità Operativa Logistica (UOL) di Genetica Medica, Ospedale Universitario S. Anna, Ferrara, Italia, retired) for his expert revision of the paper.

Declaration of interest

This study was supported in part by a Fondo di Ateneo per la Ricerca Scientifica (FAR) grant from the University of Ferrara, Ferrara, Italy. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.