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Background <p>With the widespread application of third-generation sequencing (TGS) technology, an increasing number of rare or previously unreported β-globin gene variants have been discovered. This study aims to characterize two rare complex β-globin gene variants identified in the Chinese population using TGS, aiming to enrich the spectrum of globin gene variations in this ethnic group.</p> Methods <p>Two unrelated Chinese families residing in Fujian Province were recruited for this study. Hematological screening was conducted via routine blood tests and capillary hemoglobin (Hb) electrophoresis. To detect both common and rare globin gene variants, a combination of conventional thalassemia gene detection, TGS, gap-PCR, and Sanger sequencing was employed.</p> Results <p>Hematological screening of the proband from Family 1 revealed a decreased Hb level (102&#xa0;g/L), elevated Hb A2 (9.3%), and an abnormal Hb band in zone 10. TGS identified a rare ααα<sup>anti4.2</sup> variant co-existing with Hb Stockholm [β7(A4)Glu &gt; Asp; HBB:c.24G &gt; T] in this proband. Pedigree analysis showed that the proband’s 6-month-old daughter inherited the ααα<sup>anti4.2</sup> variant (presenting with reduced MCV and MCH) but without Hb variant. The 29-year-old female proband from Family 2 exhibited remarkably reductions in MCV, MCH, and Hb A2, along with an abnormal Hb band in zone 12. Conventional testing detected the common –<sup>SEA</sup> deletion, while TGS further identified an additional rare Hb Pyrgos [β83(EF7)Gly &gt; Asp; HBB:c.251G &gt; A] variant combined with a rare IVS-II-180(T &gt; C) (HBB:c.315 + 180&#xa0;T &gt; C) variant in the proband.</p> Conclusion <p>This study is the first to describe these two rare complex Hb variants in the Chinese population. Our findings expand the knowledge of rare Hb variants and further strengthen the clinical utility of TGS in thalassemia gene testing.</p>

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First clinical and molecular characterization of two rare complex β-globin variants in Chinese population using third generation sequencing

  • 期刊论文

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  • 发表日期：

    2026年4月9日

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  • Lixian Zhang,
  • Jianlong Zhuang,
  • Nan Huang,
  • Wanyu Fu,
  • Chunnuan Chen

摘要

Background

With the widespread application of third-generation sequencing (TGS) technology, an increasing number of rare or previously unreported β-globin gene variants have been discovered. This study aims to characterize two rare complex β-globin gene variants identified in the Chinese population using TGS, aiming to enrich the spectrum of globin gene variations in this ethnic group.

Methods

Two unrelated Chinese families residing in Fujian Province were recruited for this study. Hematological screening was conducted via routine blood tests and capillary hemoglobin (Hb) electrophoresis. To detect both common and rare globin gene variants, a combination of conventional thalassemia gene detection, TGS, gap-PCR, and Sanger sequencing was employed.

Results

Hematological screening of the proband from Family 1 revealed a decreased Hb level (102 g/L), elevated Hb A2 (9.3%), and an abnormal Hb band in zone 10. TGS identified a rare αααanti4.2 variant co-existing with Hb Stockholm [β7(A4)Glu > Asp; HBB:c.24G > T] in this proband. Pedigree analysis showed that the proband’s 6-month-old daughter inherited the αααanti4.2 variant (presenting with reduced MCV and MCH) but without Hb variant. The 29-year-old female proband from Family 2 exhibited remarkably reductions in MCV, MCH, and Hb A2, along with an abnormal Hb band in zone 12. Conventional testing detected the common –SEA deletion, while TGS further identified an additional rare Hb Pyrgos [β83(EF7)Gly > Asp; HBB:c.251G > A] variant combined with a rare IVS-II-180(T > C) (HBB:c.315 + 180 T > C) variant in the proband.

Conclusion

This study is the first to describe these two rare complex Hb variants in the Chinese population. Our findings expand the knowledge of rare Hb variants and further strengthen the clinical utility of TGS in thalassemia gene testing.