The comprehensive analysis of thalassemia alleles (CATSA) based on single-molecule real-time technology (SMRT) is a more powerful strategy in the diagnosis of thalassemia caused by rare variants

Thalassemia is one of the most widely distributed monogenic disorders in the world and affects the largest number of people. It can manifest a wide spectrum of phenotypes from asymptomatic to fatal, which is associated with the degree of imbalance between alpha- and beta-globin chains. Therefore, individuals with different genotypes could present with a similar phenotype. Genetic analysis is always needed to make a correct diagnosis. However, routine genetic analysis of thalassemia used in the Chinese population identifies only 23 common variants, resulting in many cases undiagnosed or being misdiagnosed. In this study, we applied a long-read sequencing-based approach termed comprehensive analysis of thalassemia alleles (CATSA) to 30 subjects whose hematologic screening results could not be explained by the routine genetic test results. The identification of additional variants and the correction of genotypes allowed the interpretation of the clinical phenotype in 24 subjects, which have been confirmed to be correct by independent experiments. Moreover, we identified a novel 8.4-kb deletion containing the entire HBB and HBD genes as well as part of the HBBP1 gene, expanding the genotype spectrum of beta-thalassemia. CATSA showed a great advantage over other genetic tests in the diagnosis of thalassemia caused by rare variants.

Automated summary

Thalassemia is a widely distributed monogenic disorder with diverse phenotypes, and routine genetic analysis used in China is limited in identifying common variants. A long-read sequencing-based approach called CATSA was applied in this study, successfully interpreting clinical phenotypes of 24 subjects that couldn't be explained by routine genetic testing.