{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,14]],"date-time":"2025-12-14T15:43:41Z","timestamp":1765727021317,"version":"3.48.0"},"reference-count":25,"publisher":"BMJ","issue":"12","funder":[{"name":"Ratchadapisek Sompotch Endowment Fund, Faculty of Medicine, Chulalongkorn University","award":["RA-MF-12\/66"],"award-info":[{"award-number":["RA-MF-12\/66"]}]},{"DOI":"10.13039\/501100010724","name":"Health Systems Research Institute","doi-asserted-by":"publisher","award":["65-089"],"award-info":[{"award-number":["65-089"]}],"id":[{"id":"10.13039\/501100010724","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009417","name":"Care-for-Rare Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009417","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Clin Pathol"],"accepted":{"date-parts":[[2024,6,20]]},"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>\n                      Analysis of the\n                      <jats:italic>F8<\/jats:italic>\n                      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\n                      <jats:italic>F8<\/jats:italic>\n                      variation correlated with HA phenotypes in Thailand.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Thai patients with HA were enrolled from seven haemophilia treatment centres during 2022\u20132023. Using peripheral blood DNA, inverse shifting-polymerase chain reaction (IS-PCR) for\n                      <jats:italic>F8<\/jats:italic>\n                      -intron 22 inversion (Inv22) and\n                      <jats:italic>F8<\/jats:italic>\n                      -intron 1 inversion (Inv1) was performed. Whole exome sequencing (WES) was explored in cases without Inv22\/Inv1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Of 124 patients with HA, 91.9% were detected with a causative\n                      <jats:italic>F8<\/jats:italic>\n                      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%\u2009CI, 1.5 to 32.6) compared with the low-risk (small insertion\/deletion, missense and splice-site) variants. Twelve patients (9.7%) harboured novel\n                      <jats:italic>F8<\/jats:italic>\n                      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).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      IS-PCR followed by WES successfully assesses\n                      <jats:italic>F8<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jcp-2024-209542","type":"journal-article","created":{"date-parts":[[2024,7,9]],"date-time":"2024-07-09T13:28:16Z","timestamp":1720531696000},"page":"855-860","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["<i>F8<\/i>\n                    variants and their genotype-phenotype correlations in Thai patients with haemophilia A: a nationwide multicentre study"],"prefix":"10.1136","volume":"78","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-5180-9846","authenticated-orcid":false,"given":"Chayanit","family":"Trirut","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1097-3482","authenticated-orcid":false,"given":"Darintr","family":"Sosothikul","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"},{"name":"Integrative and Innovative Hematology\/Oncology Research Unit, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7540-7564","authenticated-orcid":false,"given":"Rungnapa","family":"Ittiwut","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"},{"name":"Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-589X","authenticated-orcid":false,"given":"Chupong","family":"Ittiwut","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand"},{"name":"Excellence Center for Genomics and Precision Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2538-2833","authenticated-orcid":false,"given":"Sureeporn","family":"Pongsewalak","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics, Chonburi Hospital, Chonburi, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9336-6682","authenticated-orcid":false,"given":"Natsaruth","family":"Songthawee","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9840-3443","authenticated-orcid":false,"given":"Rungrote","family":"Natesirinilkul","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0006-3400","authenticated-orcid":false,"given":"Pallapa","family":"Banjerdlak","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics, Hatyai Hospital, Songkhla, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5911-5028","authenticated-orcid":false,"given":"Pokpong","family":"Na Songkhla","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology and Oncology, Department of Pediatrics, Prapokklao Hospital, Chanthaburi, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6804-9121","authenticated-orcid":false,"given":"Patcharee","family":"Komvilaisak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6257-0867","authenticated-orcid":false,"given":"Chatphatai","family":"Moonla","sequence":"additional","affiliation":[{"name":"Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, 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