Genotype-phenotype Correlation of β-Thalassemia in Croatian Patients: A Specific HBB Gene Mutations

Abstract

An analysis of genotype-phenotype correlation was performed for 14 patients with beta-thalassemia who had been registered in Referral Centre for hematology and oncology of the University Hospital Centre, Zagreb, Croatia. HBB gene mutations were determined using a gene-specific Q5 High-Fidelity PCR analysis with direct DNA sequencing of amplified transcripts. Mahidol score index used for classification of thalassemia severity was found to be low for all the patients enrolled in the study, indicating a mild β-thalassemia phenotype with no signs of disease progression. Most of the patients have already described gene mutations: IVS-II-666 C>T (HBB:c.316-185C>T) and IVS-II-16 G>C (HBB:c.315+16G>C). Each of the aforementioned mutations was found in (11/14; 78,57%) and (10/14; 71,43%) of our patients, respectively. Recently published HBB:c.9T>C mutation was found in 8 of 14 (57,14%) in our study group. IVSII-74 T>G (HBB:c.315+74T>G) is a worldwide mutation found in 6 of 14 (42.86%) of our patients. All these mutations occur among Croatian children with no obvious Indian/Near Eastern/Iranian ancestry. We also identified 7 de novo mutations (c.316-135het_dupT, c.316-133A>G, c.93-54G>A, c.316-68_316-67het_insCGG, c.316-342delA, c.316-312delT, c.316-209delT) of mild severity phenotype according to Mahidol classification score index. We did not find children or adults with thalassemia major severity phenotype.

Direct sequencing of β-globin gene reveals a rare combination of two exonic and two intronic variants in a β-thalassemia major patient: a case report

“…However, these polymorphisms are not involved in the gene expression and are assumed to be benign. However, when these benign variants are found in association with HbS, they act as likely pathogenic variants and convert the HbS phenotype to transfusion-dependent Hb S/β + -thal [ 22 , 23 ]. Another report from Turkey suggests that IVS II-16 (G>C), along with IVS II-74 (T>G), are “likely pathogenic” polymorphisms because patients with this polymorphism exhibit low levels of MCV and HbA [ 24 ].…”

The Relevance of β-Thalassemia Heterozygosity in Pediatric Clinical Practice: Croatian Experience

“…Croatia is located at the crossroads of Central Europe, the Balkans, and the Mediterranean [6]. Although at the edge of the traditional thalassemia belt, neither systemic epidemiological nor genetic studies of thalassemia syndromes in the Croatian population have been performed, and there are 2 only a few case reports and one study with a very limited number of patients [7]. This study was performed to analyze the spectrum of the β-globin gene variants and to provide baseline data useful in launching carrier screening, genetic counseling, and prenatal diagnosis of β-thalassemias in Croatia.…”

The Relevance of β-Thalassemia Heterozygosity in Pediatric Clinical Practice: Croatian Experience

“…2 only a few case reports and one study with a very limited number of patients [7]. This study was performed to analyze the spectrum of the β-globin gene variants and to provide baseline data useful in launching carrier screening, genetic counseling, and prenatal diagnosis of β-thalassemias in Croatia.…”