Abstract：
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 α- and β-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 β-thalassemia. CATSA showed a great advantage over other genetic tests in the diagnosis of thalassemia caused by rare variants.
摘要：
地中海贫血是世界上分布最广泛的单基因疾病之一，影响人数最多。它可以表现出从无症状到致命的广泛表型，这与α-和β-珠蛋白链之间的不平衡程度有关。因此,具有不同基因型的个体可以表现出相似的表型。基因分析总是需要做出正确的诊断。然而,在中国人群中使用的地中海贫血的常规遗传分析仅识别出23种常见变异，导致许多病例未被诊断或被误诊。在这项研究中,我们对30例血液学筛查结果不能用常规基因检测结果解释的受试者应用了基于长读数测序的方法,称为地中海贫血等位基因综合分析(CATSA).另外的变体的鉴定和基因型的校正允许对24名受试者的临床表型进行解释。已被独立实验证实是正确的。此外，我们发现了一个包含整个HBB和HBD基因以及部分HBBP1基因的新型8.4kb缺失，扩大β-地中海贫血的基因型谱。CATSA在诊断由罕见变异引起的地中海贫血方面比其他基因测试具有很大的优势。
