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Peer-reviewedCC BYFrontiers in medicine

Single-molecule real-time (SMRT) sequencing technology shows advantages in the clinical diagnosis of complex thalassemia

  • Ning Tang1
  • Shiqiang Luo2
  • Xingyuan Chen3
  • Jiwei Huang1
  • Xiaoni Wei1
  • Dejian Yuan1
  • Qingyan Zhong4
  • Aiping Mao5
  • Di Cui5
  • Zhong Lin2
  • Dingyuan Zeng1
5 affiliations
  1. 1Liuzhou Hospital Division of Guangzhou Women and Children's Medical Center , , ,
  2. 2The Reproductive Hospital of Guangxi Zhuang Autonomous Region, The Reproductive Health Research Center of Guangxi Zhuang Autonomous Region , ,
  3. 3Department of Laboratory Medicine, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University , , ,
  4. 4Liuzhou Key Laboratory of Thalassemia Precision Prevention and Treatment , , ,
  5. 5Berry Genomics Corporation , ,
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Abstract

Background

Thalassemia is a hereditary hemolytic anemia caused by pathogenic variants in the α- or β-globin genes, resulting in imbalanced globin chain synthesis. Clinical manifestations vary from asymptomatic carrier states to severe transfusion-dependent anemia. Current routine diagnostic methods in China, gap polymerase chain reaction (gap-PCR) and reverse dot blot hybridization (RDB), detect only 24 common variants, leading to frequent genotype-phenotype mismatches and undiagnosed cases.Results

In this study, we employed multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, and SMRT sequencing to genetically screen 30 cases of complex thalassemia, aiming to clarify the underlying genetic causes. SMRT sequencing successfully resolved 28/30 cases (93.3%), with genotypes confirmed by MLPA and Sanger sequencing. Notably, three novel deletions were identified: a 32.8-kb (--32.8, chr16:149,860-182,697) and a 5.9-kb (chr16:169,916-175,863) deletion in the α-globin gene cluster, and an 8.3-kb deletion (chr11:5,224,209-5,232,469) in the β-globin gene cluster. In addition to detecting rare single-nucleotide variants (SNVs) and large deletions, SMRT sequencing additionally identified complex structural variants that are often missed or difficult to characterize using MLPA and Sanger sequencing.Conclusions

Our findings demonstrate that SMRT sequencing offers superior resolution and diagnostic power for complex thalassemia and is a valuable tool for improving molecular diagnosis in challenging cases.

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Cite

BibTeXRIS
BibTeX
@article{tang2026singlemolecule,
  title = {{Single-molecule real-time (SMRT) sequencing technology shows advantages in the clinical diagnosis of complex thalassemia}},
  author = {Ning Tang and Shiqiang Luo and Xingyuan Chen and Jiwei Huang and Xiaoni Wei and Dejian Yuan and Qingyan Zhong and Aiping Mao and Di Cui and Zhong Lin and Dingyuan Zeng},
  journal = {Frontiers in medicine},
  year = {2026},
  month = oct,
  doi = {10.3389/fmed.2026.1833379},
  url = {https://europepmc.org/article/PMC/PMC13725906},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Single-molecule real-time (SMRT) sequencing technology shows advantages in the clinical diagnosis of complex thalassemia
AU  - Ning Tang
AU  - Shiqiang Luo
AU  - Xingyuan Chen
AU  - Jiwei Huang
AU  - Xiaoni Wei
AU  - Dejian Yuan
AU  - Qingyan Zhong
AU  - Aiping Mao
AU  - Di Cui
AU  - Zhong Lin
AU  - Dingyuan Zeng
PY  - 2026
DA  - 2026/10/19
JO  - Frontiers in medicine
DO  - 10.3389/fmed.2026.1833379
UR  - https://europepmc.org/article/PMC/PMC13725906
AB  - Background  Thalassemia is a hereditary hemolytic anemia caused by pathogenic variants in the α- or β-globin genes, resulting in imbalanced globin chain synthesis. Clinical manifestations vary from asymptomatic carrier states to severe transfusion-dependent anemia. Current routine diagnostic methods in China, gap polymerase chain reaction (gap-PCR) and reverse dot blot hybridization (RDB), detect only 24 common variants, leading to frequent genotype-phenotype mismatches and undiagnosed cases.Results  In this study, we employed multiplex ligation-dependent probe amplification (MLPA), Sanger sequencing, and SMRT sequencing to genetically screen 30 cases of complex thalassemia, aiming to clarify the underlying genetic causes. SMRT sequencing successfully resolved 28/30 cases (93.3%), with genotypes confirmed by MLPA and Sanger sequencing. Notably, three novel deletions were identified: a 32.8-kb (--32.8, chr16:149,860-182,697) and a 5.9-kb (chr16:169,916-175,863) deletion in the α-globin gene cluster, and an 8.3-kb deletion (chr11:5,224,209-5,232,469) in the β-globin gene cluster. In addition to detecting rare single-nucleotide variants (SNVs) and large deletions, SMRT sequencing additionally identified complex structural variants that are often missed or difficult to characterize using MLPA and Sanger sequencing.Conclusions  Our findings demonstrate that SMRT sequencing offers superior resolution and diagnostic power for complex thalassemia and is a valuable tool for improving molecular diagnosis in challenging cases.
SN  - 2296-858X
ER  -