title: 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 clinical care programs. Diversity of haplotypes associated with some of the β-thal mutations can be explained by in situ recombination events in Venezuela.
authors.affiliation: Laboratorio de Investigación de Hemoglobinas Anormales, Hospital Universitario de Caracas and Instituto Anatómico José Izquierdo, Universidad Central de Venezuela ,  Caracas ,  Venezuela.
authors.forename: Martha
authors.initials: M
authors.lastname: Bravo-Urquiola
authors.forename: Anabel
authors.initials: A
authors.lastname: Arends
authors.forename: Gilberto
authors.initials: G
authors.lastname: Gómez
authors.forename: Silvia
authors.initials: S
authors.lastname: Montilla
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gerard
authors.forename: Marycarmen
authors.initials: M
authors.lastname: Chacin
authors.forename: Tsouria
authors.initials: T
authors.lastname: Berbar
authors.forename: Odalis
authors.initials: O
authors.lastname: García
authors.forename: Gloria
authors.initials: G
authors.lastname: García
authors.forename: Dalia
authors.initials: D
authors.lastname: Velasquez
authors.forename: Omar
authors.initials: O
authors.lastname: Castillo
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Krishnamoorthy
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D015995:Prevalence; D014687:Venezuela / Q000453:epidemiology; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000453:epidemiology / Q000235:genetics*
chemical_list: D055544:beta-Globins