Beta-thalassemia trait associated with a heterozygous loss-of-function variant of SUPT5H in a Southern Chinese family (2024)

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Case presentation

The proband, a 30-year-old female, was referred to our unit for prenatal examination of thalassemia during the second trimester of pregnancy. Her husband was a thalassemia carrier with a heterozygous β^41/42M variant and Hb Constant Spring variant (–CS/αα). The proband exhibited elevated HbA2 levels, mild anemia and slightly decreased red cell indices, which are indicative of the β-thalassemia trait (Figure1). However, both next-generation sequencing (NGS) and the third-generation sequencing (TGS), which target the globin genes, failed to detect any suspicious mutations. Given that her husband carried a β⁰ allele and the proband was suspected to be a β-thalassemia carrier, the couple were at risk of having offspring with β-thalassemia intermedia or major. Consequently, we collected blood samples from the proband and her parents to perform a familial whole-exome sequencing (WES) for further diagnosis. No mutations in KLF1 or other known modifier genes of thalassemia were identified within the family. A novel nonsense mutation of SUPT5H (NM_ 003169.4):c.1195C > T (p.Gln399*) was reported in the proband and her father, which was confirmed by Sanger sequencing (Figure2). This mutation is classified as likely pathogenic according to the ACMG (American College of Medical Genetics and Genomics) criteria. We also identified the mutation in her elder son via Sanger sequencing (Figure2). Both her father and son exhibited similarly elevated Hb A2 levels (Figure1). The couple declined any invasive prenatal diagnosis and chose to continue the pregnancy. After the proband gave birth, we sequenced the globin genes and SUPT5H of the neonate. Fortunately, the infant did not inherit any variant of HBB or SUPT5H (Figure1).

Discussion

The gene SUPT5H encodes the human Spt5 protein, a crucial transcription elongation factor composed of 1087 amino acids. Recent studies have identified this protein as a candidate regulator of beta-globin chain synthesis.1–3 Spt5 dimerizes with Spt4 to form a highly conserved component of the DSIF complex that functions in a tissue-specific manner. The DSIF complex collaborates with the negative elongation factor to enhance transcriptional pausing at sites proximal to the promoter, possibly facilitating assembly of an elongation competent RNA polymerase II complex.2^,4 The polymerase II pausing has been proved to be important in the specification and proliferation of hematopoietic stem cells. The haploinsufficiency of human Spt5 may hinder the pause release of RNA polymerase II into productive elongation, disturbing the effective transcription of HBB and resulting in an imbalance in the synthesis of alpha and beta-globin chains.2^,5 Besides, the activity of HBB locus control region (LCR), which is involved in the regulation of high-level expression of the beta-globin, is diminished when loss-of-function mutations occur in SUPT5H.2

The clinical association between beta-thalassemia and SUPT5H mutations was first established by Achour et al. in 2020.1 To date, more than 19 variants involving SUPT5H in over 43 individuals with thalassemia traits have been reported in the literature, including nonsense, frame-shift, splice-site, missense mutations and a copy number variation (CNV).1^,3^,6 Most of the variants causing β-thal trait are loss-of-function, suggesting that haploinsufficiency of the Spt5H protein underlies the reduced expression of HBB. Almost all heterozygotes for SUPT5H variants exhibit an increased Hb A2 value, not necessarily accompanied with erythrocytic microcytosis and hypochromia. Digenic heterozygotes for variants in HBB and SUPT5H could lead to a more pronounced phenotype resembling β-thalassemia intermedia.1 According to a recent cohort study,6 mutations in SUPT5H account for a significant proportion of unlinked β-thalassemia, comparable to those of KLF1, and may cause severe symptoms when coexisting with β⁰ allele. Therefore, in regions with high prevalence of β-thalassemia, SUPT5H sequencing should be considered when we try to diagnose patients with unexplained β-thal trait especially during prenatal diagnosis.

Acknowledgements

We thank the patients and their family members for their participation in this study. We also thank Peirun Tian and Shiping Chen from BGI genomics for their technical assistance in whole-exome sequencing.

Author contributions

Xiangyuan Huang (Formal analysis [equal], Resources [equal], Writing—original draft [equal]), Lijuan Zhong (Writing—review & editing [equal]) and Rui Zhang (Conceptualization [equal], Funding acquisition [equal], Supervision [equal], Writing—review & editing [equal]).

Funding

This work was supported by Shenzhen Key Medical Discipline Construction Fund (SZXK028).

Conflict of interest

None declared.

Statement of ethics

This study was approved by the Ethics Committee of Shenzhen Baoan Women’s and Children’s Hospital (No. LLSC-2022-01-03-11-KS) in compliance with the Declaration of Helsinki. Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.

References

© The Author(s) 2024. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com

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