Abstract：
Thalassemia is one of the most common and damaging monogenic diseases in the world. It is caused by pathogenic variants of α- and/or β-globin genes, which disrupt the balance of these two protein chains and leads to α-thalassemia or β-thalassemia, respectively. Patients with α-thalassemia or β-thalassemia could exhibit a severe phenotype, with no simple and effective treatment. A three-tiered strategy of carrier screening, prenatal diagnosis and newborn screening has been established in China for the prevention and control of thalassemia, of which the first two parts have been studied thoroughly. The implementation of neonatal thalassemia screening is lagging, and the effectiveness of various screening programs has not yet been demonstrated. In this study, hemoglobin capillary electrophoresis (CE), hotspot testing method, and third-generation sequencing (TGS) were used in the variant detection of 2000 newborn samples, to assess the efficacy of these methods in neonatal thalassemia screening. Compared with CE (249, 12.45 %) and hotspot analysis (424, 21.2 %), CATSA detected the largest number of thalassemia variants (535, 26.75 %), which included 24 hotspot variants, increased copy number of α-globin gene, rare pathogenic variants, and three unreported potentially disease-causing variants. More importantly, CATSA directly determined the cis-trans relationship of variants in three newborns, which greatly shortens the clinical diagnosis time of thalassemia. CATSA showed a great advantage over other genetic tests and could become the most powerful technical support for the three-tiered prevention and control strategy of thalassemia.
摘要：
地中海贫血是世界上最常见和最具破坏性的单基因疾病之一。它是由α-和/或β-珠蛋白基因的致病变体引起的，破坏这两个蛋白质链的平衡，导致α-地中海贫血或β-地中海贫血，分别。患有α-地中海贫血或β-地中海贫血的患者可能表现出严重的表型，没有简单有效的治疗方法。载体筛查的三层策略，中国已经建立了产前诊断和新生儿筛查，以预防和控制地中海贫血，其中的前两部分已经过深入研究。新生儿地中海贫血筛查实施滞后,各种筛查方案的有效性尚未得到证实。在这项研究中,血红蛋白毛细管电泳（CE），热点测试方法，和第三代测序（TGS）用于2000个新生儿样本的变异检测，评估这些方法在新生儿地中海贫血筛查中的功效。与CE（249，12.45%）和热点分析（424，21.2%）相比，CATSA检测到的地中海贫血变异体数量最多（535，26.75%），其中包括24个热点变体，α-珠蛋白基因拷贝数增加，罕见的致病变异，和三个未报告的潜在致病变异。更重要的是,CATSA直接测定了三个新生儿中变异体的顺反关系，大大缩短了地中海贫血的临床诊断时间。CATSA相对于其他基因检测显示出巨大的优势，可能成为地中海贫血三级防控策略最有力的技术支持。
