Thalassemia Intermedia Caused by 16p13.3 Sectional Duplication in a β-Thalassemia Heterozygous Child

Abstract

Thalassemia intermedia is an inherited hemoglobin disorder characterized by a significant genetic and clinical heterogeneity. A wide spectrum of different genotypes-homozygous, heterozygous, and compound heterozygous-have been found to be responsible for it. The authors describe a Chinese child of β-thalassemia heterozygote with the mutation IVS2-654 (C→T) (HBB:c.316-197C→T) presenting with severe thalassemia intermedia. Multiplex ligation-dependent probe amplification (MLPA) and array comparative genomic hybridization (CGH) analyses of the α gene cluster revealed an approximate 146-kb duplication at 16p13.3 including the complete α gene cluster. The duplicated allele and the normal allele in trans result in a total of 6 active α genes. The severe clinical phenotype seemed to be related to the considerable excess of the α-globin and the β-globin deficit caused by the presence of the β-thalassemia. The α gene duplication should be considered in patients heterozygous for β-thalassemia who show a more severe phenotype than β-thalassemia trait.

Next‐generation sequencing as a tool for breakpoint analysis in rearrangements of the globin gene clusters

“…Probes are not placed in repetitive regions of the genome, and the assay is not able to detect balanced rearrangements. CGH array has been used with some success to detect SVs causing hemoglobinopathies …”

Beta thalassaemia intermedia due to co‐inheritance of three unique alpha globin cluster duplications characterised by next generation sequencing analysis

“…To date, seven other segmental HBA cluster duplications have been documented, including the anti‐3·7 and ‐4·2 triplicated HBA genes (Sollaino et al , ; Harteveld & Higgs, ; Jiang et al , ; Liu et al , ). These three additional cases take the total to 10 (Fig ).…”

Complex interactions between thalassemia defective alleles compromise screening and cause severe anemia in a Chinese family

“…Copy number variations in the form of multiplications of α genes can cause a severe phenotype in β‐thalassemia carriers due to accentuation of α/β globin chain imbalance. Previous studies, including our two cases, showed that six active α genes could result in severe β‐thalassemia intermedia or β‐thalassemia major in β‐thalassemia heterozygotes. These might be the reason, at least, for a part of the many unclear cases of severe phenotype in β‐thalassemia carriers.…”