Two novel copy number variations involving the α-globin gene cluster on chromosome 16 cause thalassemia in two Chinese families

Copy number variations (CNVs) can cause many genetic disorders and the structure analysis of unknown CNVs is important for clinical diagnosis. The human alpha-globin gene cluster lies close to the telomere of the short arm on chromosome 16. Copy number variations of this region produce excessive or insufficient alpha-globin chains which imbalances the beta-globin chains, resulting in thalassemia. However, these CNVs usually cannot be precisely defined by traditional methods. Here, we designed a technique strategy and applied it to identify two CNVs involving the alpha-globin gene cluster causing thalassemia in two Chinese families. A novel 282 kb duplication (alpha alpha alpha alpha(282)) was identified in family A and a novel 235 kb deletion (--(235)) in family B. Proband A is a coinheritance of beta(CD41-42) and alpha alpha alpha alpha(282) and showed severe beta-thalassemia intermedia phenotype. Proband B is a compound heterozygote of --(235)/alpha(CS)alpha genotype and was diagnosed with hemoglobin H disease. The clinical phenotypic features of the CNVs carriers were described, together with a complete picture of molecular structure of these rearrangements. Two CNVs are novel rearrangements in alpha-globin clusters and the alpha alpha alpha alpha(282) is the first to identify the exact insert position of a duplication region from the telomere on chromosome 16. In a conclusion, successful identification and characterization of these two novel CNVs not only demonstrates the precision and effectiveness of our strategy in analyzing the structure of unknown CNVs, but also extended the spectrum of thalassemia and provide new examples for studying genomic recombination.