RT Journal Article SR Electronic T1 F8 variants and their genotype-phenotype correlations in Thai patients with haemophilia A: a nationwide multicentre study JF Journal of Clinical Pathology JO J Clin Pathol FD BMJ Publishing Group Ltd and Association of Clinical Pathologists SP jcp-2024-209542 DO 10.1136/jcp-2024-209542 A1 Trirut, Chayanit A1 Sosothikul, Darintr A1 Ittiwut, Rungnapa A1 Ittiwut, Chupong A1 Pongsewalak, Sureeporn A1 Songthawee, Natsaruth A1 Natesirinilkul, Rungrote A1 Banjerdlak, Pallapa A1 Na Songkhla, Pokpong A1 Komvilaisak, Patcharee A1 Moonla, Chatphatai A1 Suphapeetiporn, Kanya YR 2024 UL http://jcp.bmj.com/content/early/2024/07/09/jcp-2024-209542.abstract AB 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.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.