Tang Haishen, Xiong Yi, Tang Jiaqi, Wang Xiaohong, Wang Ya, Huang Liping, Wang Runli, Wang Degang
From the Prenatal Diagnosis Center, Boai Hospital of Zhongshan, Zhongshan, China (H. Tang, Xiong, D. Wang).
the Second School of Clinical Medicine, Southern Medical University. Guangzhou, China (H. Tang, Xiong, J. Tang, X. Wang, D. Wang).
Arch Pathol Lab Med. 2025 Jan 1;149(1):e1-e10. doi: 10.5858/arpa.2023-0382-OA.
CONTEXT.—: Rare thalassemia subtypes are often undiagnosed because conventional testing methods can only identify 23 common types of α- and β-thalassemia.
OBJECTIVE.—: To assess a comprehensive approach for the screening and diagnosis of rare thalassemia.
DESIGN.—: The study cohort included 72 individuals with suspected rare thalassemia variants. Screening was conducted by next-generation sequencing (NGS) combined with third-generation sequencing (TGS) and chromosomal microarray analysis (CMA)/copy number variation sequencing.
RESULTS.—: Of the 72 individuals with suspected rare thalassemia, 49 had rare α- or β-gene variants. NGS combined with gap polymerase chain reaction detected a total of 42 cases, resulting in a positive detection rate of 58.3%. Additionally, 4 α-globin genetic deletions were identified by TGS, which increased the variant detection rate by 5.6%. Two samples with a microdeletion of chromosome 16 or 11 were detected by CMA, which increased the detection rate by 2.8%. For one sample, reanalysis of the NGS and TGS data confirmed the presence of the β41-42/βN and βN/βN mosaic. The HBB:c.315 + 2delT mutation was initially reported in Guangdong Province, China. Two HBB gene mutations (HBB:c.315 + 5G>C and HBB:c.295G>A) and 4 rare HBA gene deletions (-11.1, -α27.6, -α2.4, and -α21.9) were initially identified in the Zhonshan region. The hematologic phenotypes of all rare cases in this study were clarified.
CONCLUSIONS.—: Rare thalassemia variants are more common than previously thought. Despite advancements in TGS, there is still no foolproof method for detection of all types of thalassemia. Thus, a comprehensive approach is necessary for accurate screening and diagnosis of rare thalassemia variants.
罕见的地中海贫血亚型往往未被诊断出来，因为传统检测方法只能识别23种常见的α和β地中海贫血类型。
评估一种用于罕见地中海贫血筛查和诊断的综合方法。
研究队列包括72名疑似患有罕见地中海贫血变异的个体。通过下一代测序（NGS）结合第三代测序（TGS）和染色体微阵列分析（CMA）/拷贝数变异测序进行筛查。
在72名疑似患有罕见地中海贫血的个体中，49名存在罕见的α或β基因突变。NGS结合缺口聚合酶链反应共检测出42例，阳性检出率为58.3%。此外，通过TGS鉴定出4例α珠蛋白基因缺失，使变异检出率提高了5.6%。通过CMA检测出2例16号或11号染色体微缺失样本，使检出率提高了2.8%。对于一个样本，对NGS和TGS数据的重新分析证实了β41-42/βN和βN/βN嵌合体的存在。HBB:c.315 + 2delT突变最初在中国广东省被报道。两个HBB基因突变（HBB:c.315 + 5G>C和HBB:c.295G>A）以及4种罕见的HBA基因缺失（-11.1、-α27.6、-α2.4和-α21.9）最初在中山地区被鉴定出来。本研究中所有罕见病例的血液学表型均得以明确。
罕见的地中海贫血变异比之前认为的更为常见。尽管TGS有了进展，但仍没有能检测出所有类型地中海贫血的万无一失的方法。因此，对于罕见地中海贫血变异的准确筛查和诊断，综合方法是必要的。
