Genetic Heterogeneity of Alpha - and Beta - Globin Mutations in a German Multiethnic Population Group

Abstract 5185

Thalassemia syndromes are among the most common hereditary diseases worldwide and are widespread throughout the Mediterranean Region, Africa, the Middle East, India, Burma, the Southeast Asia and Indonesia. Similarly, hemoglobinopathies are common in different ethnic groups and mixed syndromes of Thalassemia and hemoglobinopathies exist.

In this retrospective study we report the number and type of Thalassemia mutations and their combination with hemoglobinopathies detected mostly in individuals with a migration background now living in Germany.

DNA samples were analyzed by polymerase chain reaction (PCR) and direct DNA-sequencing and additionally by multiplex ligation-dependent amplification (MRC-HOLLAND MLPA®).

Mutations in one or both beta-globin chains were found in 77 patients. Most of these mutations were beta Thalassemia mutations, n=41 (Thalassemia minor n=33, Thalassemia major/intermedia n=7, homozygous Quin-Hai Hemoglobinopathy n=1).

In 34 samples we found the hemoglobin S single base mutation c. 20A>T p. E7V, either alone or in combination with a hemoglobin C mutation c. 19G>A p. E7K or beta Thalassemia mutation (HbAS n=14, HbSS n=12, HbSC n=6, HbSThal n=2).

In two patients we found only the hemoglobin C mutation by itself (HbAC n=1, HbCC n=1).

In 52 samples we found mutations on the alpha-globin chains, most often the 3. 7KB deletion (n=27), followed by the SEA (n=4), the 20. 5 KB deletion (n=4), the 4. 2 KB deletion (n=4), the Dutch deletion (n=3) and alpha triplication (n=3). Two of the remaining seven samples showed new alpha Thalassemia mutations which have not been described yet.

In an additional 34 DNA samples we found a combination of alpha- and beta-globin chain changes. In 4 of these samples we detected new mutations in the alpha-globin chains.

The prevalence of mutations in the alpha- and beta-globin chains varies greatly because of a complex ethnic structure of our patients. Changes of the alpha-globin chains could not be safely detected by hemoglobin-electrophoresis. These situations are very important for genetic counseling in a population in which consanguineous marriages are common. Furthermore, alpha-globin mutations are genetic modifiers for beta Thalassemia and sickle cell disease and will influence the phenotype of beta-globin chain mutations. Patients with a compound heterozygous mutation for beta Thalassemia will probably not be detected by hemoglobin-electrophoresis alone, as in milder forms and early childhood the hemoglobin is not severely decreased and hemoglobin electrophoresis may be misinterpreted for Thalassemia minor.

Our findings underline the heterogeneity of beta-globin and alpha-globin chain mutations and the importance of hematological and molecular analyses in the diagnosis and genetic counseling.