{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"
      ],
      "name": "Chayanit Trirut"
    },
    {
      "affiliations": [
        "Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand",
        "Integrative and Innovative Hematology/Oncology Research Unit, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"
      ],
      "name": "Darintr Sosothikul"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand",
        "Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"
      ],
      "name": "Rungnapa Ittiwut"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand",
        "Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"
      ],
      "name": "Chupong Ittiwut"
    },
    {
      "affiliations": [
        "Division of Pediatric Hematology and Oncology, Department of Pediatrics, Chonburi Hospital, Chonburi, Thailand"
      ],
      "name": "Sureeporn Pongsewalak"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand"
      ],
      "name": "Natsaruth Songthawee"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"
      ],
      "name": "Rungrote Natesirinilkul"
    },
    {
      "affiliations": [
        "Division of Pediatric Hematology and Oncology, Department of Pediatrics, Hatyai Hospital, Songkhla, Thailand"
      ],
      "name": "Pallapa Banjerdlak"
    },
    {
      "affiliations": [
        "Division of Pediatric Hematology and Oncology, Department of Pediatrics, Prapokklao Hospital, Chanthaburi, Thailand"
      ],
      "name": "Pokpong Na Songkhla"
    },
    {
      "affiliations": [
        "Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand"
      ],
      "name": "Patcharee Komvilaisak"
    },
    {
      "affiliations": [
        "Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand",
        "Center of Excellence in Translational Hematology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"
      ],
      "name": "Chatphatai Moonla"
    },
    {
      "affiliations": [
        "Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand",
        "Division of Medical Genetics and Metabolism, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand"
      ],
      "name": "Kanya Suphapeetiporn"
    }
  ],
  "title": "F8 variants and their genotype-phenotype correlations in Thai patients with haemophilia A: a nationwide multicentre study",
  "uid": "67d9affa-1bf2-5004-a1ef-e0ab5e6b5464"
}