Two Novel Mutations in the α-Globin Genes Leading to α-Thalassemia.

Although deletional α-thalassemia is the most common form of the disease worldwide, in Israel, point mutations leading to α-thalassemia are relatively common. We routinely sequence the α-globin genes when we fail to find deletions which can account for the hematological phenotype. Our PCR is specific for sequencing either the α1 or α2 globin gene. We here report two novel mutations, one in α1 and the other in α2, which lead to a thalassemia phenotype. Case 1. A 5 yr old Druze girl from northern Israel was referred due to microcytic anemia. Her hematological values were: RBC 5x109/L, Hb 8.8 gr%, MCV 55 fl, MCH 17.6 pg, MCHC 31.7gr/dl, RDW 16.2. HbA 2: 2.2%, HbF: 1%. Iron deficiency was excluded (serum iron: 58 mg/dl, transferrin: 247mg%, and ferritin: 46.2 ng/ml) The patient’s physical examination and mental development were normal, without splenomegaly or jaundice. No therapy was required, and transfusion was unnecessary. The parents had very mild microcytic anemia (mother Hb 11 gr% MCV 75.5, father Hb 13.8, MCV 78.6) with normal Hb electrophoresis. DNA of the parents and propositus was sequenced. The child was found to be homozygous (and the parents, heterozygous) for a deletion of a single cytosine (within a stretch of four) at codons 118/119 of the α2 globin gene, leading to a frameshift at codon 119. Case 2. This family is of mixed ancestry, the mother is from Bukhara. The hematological data is presented in the table below. Sequencing of the α-globin genes of the mother revealed an A to G change at the acceptor site of IVS1 at nt 116 in the α1 gene in compound heterozygosity with the well known 5 nt deletion in IVS1 of α2 (HphI). The same IVS1 nt 116 mutation at this exact nucleotide was previously reported by Harteveld (1996) to be found in the α2 globin gene, causing Hb H inclusion bodies when found in combination with 3.7 kb deletional α-thalassemia. We conclude that rare point mutations can still be identified in the α-globin genes which can be the cause of otherwise unexplained α-thalassemia phenotypes. Family 2 hematological data and alpha globin genotype Family member RBC Hb MCV MCH RDW chromosome 1 chromosome 2 del=deletion Mother 5.68 10.7 63.2 18.8 16.4 α2 HphI α1 IVS1-116 Father 6.15 13.4 70.7 21.8 13.9 del 3.7kb del 3.7 kb Son (9 yrs) 5.59 11.1 64.4 19.9 13.7 α2 HphI del 3.7 kb Daughter (7 yrs) 5.44 10.9 64.3 20.0 13.5 del 3.7 kb α1 IVS1-116 Son (2 yrs) 5.55 10.5 61.6 18.9 14.3 del 3.7 kb α1 IVS1-116