De novo initiation codon mutation (ATG→ACG) of the β‐globin gene causing β‐thalassemia in a swiss family

Investigation of microcytic anemia with normal ferrous status in two members (father and daughter) of a Swiss family originating from Bern revealed high levels of HbA2 (4%, 7.3%) and HbF (3.2%, 3.1%). Direct sequence analysis of asymmetrically amplified DNA showed the ATGǍG mutation in the initiation codon of the β-globin gene. Heterozygous β-thalassemia was not found in either of the propositus's parents or in any of his brothers and sisters. Extended restriction fragment length polymorphism haplotyping of the β chromosomes led us to the conclusion of a recent spontaneous mutation in the paternal germ cell. The results of routine HLA and blood group testing supported the stated paternity. We also found that the intragenic sequence polymorphisms (frameworks) are not always in linkage disequilibrium with the Bam HI polymorphism downstream from the β-globin gene as previously observed. This is the second family found to carry this initiation codon mutation in the β-globin gene. Unlike the first reported family, of Yugoslavian origin, our patients have high HbF levels and this in the absence of a C→T substitution at-158 site 5′to Gγ. © 1993 Wiley-Liss, Inc.