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Poster Networking

Inherited Bleeding Disorders and Inhibitors

PB0222 - F8 variants and their genotype-phenotype correlations in Thai patients with hemophilia A: A nationwide multicenter study

Sunday, June 23, 2024
13:45 – 14:45 ICT
Room: Exhibition Hall

    Presenting Author(s)

  • CT

    Chayanit Trirut

    Specialized Physician
    Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
    Bangkok, Krung Thep, Thailand

    • Co-Author(s)

  • Darintr Sosothikul, MD

    Professor
    Chulalongkorn University
    Pathumwan, Krung Thep, Thailand

  • RI

    Rungnapa Ittiwut

    Research scientist
    Excellence Center of Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
    Bangkok, Krung Thep, Thailand

  • CI

    Chupong Ittiwut

    Research scientist
    Excellence Center of Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand
    Bangkok, Krung Thep, Thailand

  • SP

    Sureeporn Pongsewalak

    Specialized Physician
    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Chonburi hospital, Chonburi, Thailand
    Chon Buri, Chon Buri, Thailand

  • NS

    Natsaruth Songthawee

    Specialized Physician
    Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkla, Thailand
    Hat Yai, Songkhla, Thailand

  • RN

    Rungrote Natesirinikul

    Associate Professor
    Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
    Chiang Mai, Chiang Mai, Thailand

  • PB

    Pallapa Banjerdlak

    Specialized Physician
    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Had Yai Hospital, Songkla,Thailand
    Had yai, Songkhla, Thailand

  • PN

    Pokpong Na Songhhla

    Specialized Physician
    Division of Pediatric Hematology and Oncology, Department of Pediatrics, Pra Pok Klao Hospital, Chanthaburi, Thailand
    Chanthaburi, Chanthaburi, Thailand

  • Patcharee Komvilaisak, Associate professor

    Instructor
    Department of Pediatrics, Srinagarind Hospital, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
    Muang, Khon Kaen, Thailand

  • Chatphatai Moonla, MD, MSc

    Hematologist
    Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA

  • KS

    Kanya Suphapeetiporn

    Professor
    Center Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkomn University, Bangkok, Thailand
    Bangkok, Krung Thep, Thailand

Background: Genetic assessment of the F8 gene presents an opportunity to predict risk of developing factor VIII (FVIII) inhibitors and depth of phenotype severity among hemophilia A (HA) patients. However, data in Southeast Asian countries are scarce.

Aims: To study genetic variation of the F8 gene correlated with HA phenotypes in Thailand.

Methods: Thai HA patients were enrolled from 7 hemophilia treatment centers 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 subsequently explored in cases without Inv22/Inv1.

Results: Of 124 patients from 119 families (75.0% severe HA; median age at diagnosis 0.75 years [interquartile range, 0.50-1.94]), 91.9% were detected with a causative F8 variant (Figure 1). Overall, Inv22 (30.6%) was the most prevalent, followed by missense (23.4%), nonsense (16.9%), and small insertion/deletion (16.1%) variants. Exon mutations in 70 patients distributed in either heavy chain (50.0%), light chain (48.6%), or signal peptide (1.4%) sequences. Patients with Inv22, small insertion/deletion, and nonsense variants were associated with severe HA, compared to those with missense variants, by the odds ratios (OR) of 13.9 (95% confidence interval [CI], 4.2-56.7), 14.7 (95% CI, 3.4-104.7), and 15.6 (95% CI, 3.6-110.2), respectively. While patients with nonsense light-chain mutations increased risk of developing FVIII inhibitors (OR 6.8; 95% CI, 1.5-32.6) compared to those with the low-risk (small insertion/deletion, missense, and splice-site) mutations. Among 12 patients (9.7%), novel F8 variants, including 5 missense (p.Pro540Leu, p.Ser564Pro, p.Leu668Pro, p.Ala1721Glu, p.His2024Pro), 5 small insertion/deletion (p.Val502SerfsTer13, p.Ile522PhefsTer13, p.Phe992LysfsTer11, p.Leu1223PhefsTer18, c.6427_6429+3delATGGTA), and 1 nonsense (p.Glu1292Ter) variants, were identified.

Conclusion(s): IS-PCR followed by WES can successfully assess F8 mutations in most HA cases. With several unique variants, severe HA in Thailand is considerably caused by Inv22, small insertion/deletion, and nonsense mutations, whereas missense mutations are more responsible for nonsevere HA phenotype.