Beta thalassemia in Germany: molecular genetics and clinical phenotype in immigrant and in the native population

Abstract

In Germany there are about 300-400 patients with homozygous beta-thalassaemia who immigrated from endemic regions mostly in the Mediterranean. In the non-immigrant population beta-thalassaemia is rare with only single case reports of homozygous patients. Heterozygous beta-thalassaemia, however, is more common and must be considered in the differential diagnosis of hypochromic anemia. Here, clinical and molecular data of 221 homozygous patients from immigrant families and 256 non-immigrant German heterozygous individuals are presented. Clinically, 87% (n = 192) of the homozygotes are regularly transfused and classified as thalassaemia major (TM). The other 13% (n = 29) are not (regularly) transfused and thus classified as thalassaemia intermedia (TI). There is a wide spectrum of 39 beta-globin gene mutations and even the most common three, IVSI-110G-A, NS 39, and IVSI-6 T-C occur with relatively low frequencies of 28%, 22%, and 9%, respectively. In 17/29 (58%) TI patients "mild" mutations are found that inactivate the affected gene incompletely. In 16/29 (55%) there are mutations that are associated with increased gamma-globin gene activity. alpha-Thalassaemia is rare and only found in 3/29 TI-patients. In the 256 Germans with heterozygous beta-thalassaemia there are 27 different beta-globin gene mutations. The 3 most common are Mediterranean mutations together accounting for 61%. Also-relatively common (5%; n = 13) is an otherwise rare frameshift mutation of codon 83 (FS83 delta G). The other mutations occur in < 10 individuals only. Two mutations described here are novel. One of them affects position-2 of the intron 1 splice acceptor site (IVSI-129 A-G) and the other is a deletion of a single G in codon 15/16 (FS 15/16 delta G). Taken together, a plausible molecular pathogenesis for the observed phenotype (TM vs. TI) can be identified in most homozygous patients thus allowing for rational counselling of the affected families. In heterozygous Germans beta-thalassaemia has probably been imported from the Mediterranean in about 2/3 of the cases whereas in the remaining 1/3 it has probably originated locally.