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F8 variants and their genotype-phenotype correlations in Thai patients with haemophilia A: a nationwide multicentre study
  1. Chayanit Trirut1,
  2. Darintr Sosothikul2,3,
  3. Rungnapa Ittiwut1,4,
  4. Chupong Ittiwut1,4,
  5. Sureeporn Pongsewalak5,
  6. Natsaruth Songthawee6,
  7. Rungrote Natesirinilkul7,
  8. Pallapa Banjerdlak8,
  9. Pokpong Na Songkhla9,
  10. Patcharee Komvilaisak10,
  11. Chatphatai Moonla11,12,
  12. Kanya Suphapeetiporn4,13
  1. 1 Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  2. 2 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  3. 3 Integrative and Innovative Hematology/Oncology Research Unit, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  4. 4 Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
  5. 5 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Chonburi Hospital, Chonburi, Thailand
  6. 6 Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
  7. 7 Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
  8. 8 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Hatyai Hospital, Songkhla, Thailand
  9. 9 Division of Pediatric Hematology and Oncology, Department of Pediatrics, Prapokklao Hospital, Chanthaburi, Thailand
  10. 10 Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
  11. 11 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
  12. 12 Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  13. 13 Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
  1. Correspondence to Professor Darintr Sosothikul, Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand; dsosothikul{at}hotmail.com; Darintr.S{at}chula.ac.th

Abstract

Aims Analysis of the F8 gene helps predict the risk of developing factor VIII (FVIII) inhibitors and the depth of phenotype in haemophilia A (HA) patients. Since data in Southeast Asian countries remain scarce, we aim to study F8 variation correlated with HA phenotypes in Thailand.

Methods Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022–2023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for F8-intron 22 inversion (Inv22) and F8-intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22/Inv1.

Results Of 124 patients with HA, 91.9% were detected with a causative F8 variant, including Inv22 (30.6%), Inv1 (1.6%), missense (23.4%), nonsense (16.9%) and small insertion/deletion (16.1%) mutations. Inv22, small insertion/deletion and nonsense were associated with severe HA, compared with missense variants, by the ORs of 13.9 (95% CI, 4.2 to 56.7), 14.7 (95% CI, 3.4 to 104.7) and 15.6 (95% CI, 3.6 to 110.2), respectively. While nonsense variants affecting the light chain increased the risk of developing FVIII inhibitors (OR, 6.8; 95% CI, 1.5 to 32.6) compared with the low-risk (small insertion/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel F8 variants, comprising five missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), five small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA) and one nonsense mutations (p.Glu1292Ter).

Conclusions IS-PCR followed by WES successfully assesses F8 alterations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion and nonsense, whereas missense variants are more responsible for nonsevere HA phenotypes.

  • Genetic Diseases, Inborn
  • Hemophilia A
  • Hemostasis

Data availability statement

Data are available upon reasonable request. CT and DS have full access to all data and take responsibility for the integrity and accuracy of data.

https://doi.org/10.1136/jcp-2024-209542

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    Data availability statement

    Data are available upon reasonable request. CT and DS have full access to all data and take responsibility for the integrity and accuracy of data.

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    Footnotes

    • Handling editor Vikram Deshpande.

    • Contributors CT designed the study, collected samples and clinical data, analysed data and wrote the first draft of the manuscript. DS designed the study, collected samples and clinical data, analysed data, critically reviewed and wrote the manuscript and was responsible for the overall content as the guarantor. RI and CI performed DNA extraction and molecular assays, and analysed bioinformatic data. SP, NS, RN, PB, PNS and PK collected samples and clinical data, critically reviewed and wrote the manuscript. CM analysed data, critically reviewed and wrote the manuscript. KS remarked on the whole exome sequencing results, critically reviewed and wrote the manuscript. All authors read and approved the final version of the manuscript.

    • Funding This research was supported by the Ratchadapisek Sompotch Endowment Fund, Faculty of Medicine, Chulalongkorn University (grant no. RA-MF-12/66); the Health Systems Research Institute (grant no. 65-089) and the Care-For-Rare Foundation.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.