ClinVar Genomic variation as it relates to human health

Weatherall et al. (1973) described an Irish family with an unusual form of beta-thalassemia (613985) that was characterized by anemia, splenomegaly, and gross abnormalities of the erythrocytes and their precursors; the disorder was transmitted through several generations in an autosomal dominant fashion. Initially the disorder was labeled dyserythropoietic anemia, congenital, Irish or Weatherall type (603902). Thein et al. (1990) restudied the Irish family and 3 similarly affected kindreds, all of Anglo-Saxon origin, and pointed to similar cases reported by others and to the fact that the designation inclusion body beta-thalassemia had been proposed (Stamatoyannopoulos et al., 1974). All affected members of the original Irish family had a moderate anemia with splenomegaly, increased levels of Hb A2 and Hb F, and increased alpha/beta chain synthesis ratios. Two family members had undergone splenectomy. By the time of the report of Thein et al. (1990), 1 family member had died, showing at autopsy extensive extramedullary hemopoiesis and iron overload in parenchymal tissues in a pattern typical of excessive iron absorption rather than transfusion. The family had a complex rearrangement in the third exon of the HBB gene that involved 2 deletions, 1 of 4 bp in codons 128 and 129 and the other of 11 bp in codons 132-135. The deletions were interrupted by an insertion of 5 bp, CCACA, followed by the normal sequence of 8 nucleotides. The modification resulted in a frameshift reading through to codon 153, predicting the synthesis of a variant beta-globin 7 residues longer than normal. Thein et al. (1990) suggested that the phenotypic difference between this condition and the more common recessive forms of beta-thalassemia lies mainly in the length and stability of the abnormal translation products that are synthesized and, in particular, whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation. (less)