MOLECULAR SPECTRUM OF β-THALASSEMIA MUTATIONS IN THE ADMIXED VENEZUELAN POPULATION, AND THEIR LINKAGE TO β-GLOBIN GENE HAPLOTYPES

Abstract

In order to establish the spectrum of β-thalassemia (β-thal) mutations in the Venezuelan population for the first time, 127 unrelated subjects either with a suspicion of β-thal trait or with a clinically recognized β-thal syndrome of different degrees of severity, were studied. DNA from these subjects was analyzed by a polymerase chain reaction (PCR)-based reverse dot-blot method or amplification refractory mutation system (ARMS). Prototype β-globin gene sequencing of relevant DNA was performed to confirm the mutations. Fifteen different mutations were identified accounting for 92.0% of the mutant alleles explored, revealing a significant genetic heterogeneity at the β-globin gene locus in this population. The most frequent mutations were codon 39 (C >T) 34.1%, IVS-I-1 (G >A) 11.1%, IVS-I-6 (T > C) 6.6%, IVS-I-110 (G >A) 6.6%, IVS-II-849 (A >G) 6.6%, 88 (C >T) 6.0%, 29 (A >G) 5.2%, followed by the less common IVS-I-5 (G >A) 3.7%, the 1,393 bp deletion 3.0%, IVS-II- 1 (G>A) 3.0%, 86 (C >G) 2.2%, IVS-II-1 (G >T) 1.5%, codons 41/42 (–TCTT) 1.5%, IVS-II- 745 (C >G) 0.7% and deletional δβ-thal 0.7%. Overall, these data demonstrate that the major sources of β-thal alleles in Venezuela, as expected, are of Mediterranean and African origins. This is the first large study defining the molecular spectrum of β-thal in the highly admixed population of Venezuela and lays the foundation for genetic counseling as well as implementing comprehensive