Deleterious variants cluster in the A3 domain of factor VIII in people with severe hemophilia A and inhibitors
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background Hemophilia A (HA) is an X-linked disorder due to deleterious variants in the factor VIII (FVIII) gene ( F8 ). Few studies from large cohorts have explored F8 genotype in people with HA with origins other than North American and European. Objectives We aimed to evaluate the spectrum of F8 variants and haplotypes and affected FVIII domains and chains in the context of inhibitor development in people with severe hemophilia A. Methods We performed genotyping of intron 1 and intron 22 inversions (Inv22) and F8 sequencing using a customized gene panel and whole exome sequencing. Results We included 265 people with severe hemophilia A. We identified deleterious variants in 98.1% of them, totaling 97 unique mutations, of which 32 (33.0%) are novel. Inv22, nonsense, small insertion/deletion, large deletion, and missense variants accounted for 48.3%, 14.7%, 11.3%, 9.8%, and 7.5% of the variants identified. Variants clustered in the FVIII A3 domain were more often associated with people with HA with inhibitors (INH+) than those without inhibitors (INH−) (21.0% vs 0.0%; P < .001); variants clustered in the A1 domain were more often associated with INH− than with INH+ individuals (33.3% vs 7.7% ; P < .001). Inv22 was associated with a 4.8-fold increased risk of developing inhibitors in previously untreated patients (odds ratio, 4.81; 95% CI, 2.02-12.01). Conversely, missense variants protected against inhibitor development (odds ratio, 0.09; 95% CI, 0.01-0.50). Conclusion These findings highlight the role of F8 genotype and specific FVIII domains in inhibitor development in an admixed population of people with HA. This could help engineer therapeutic approaches targeting FVIII molecules with reduced immunogenicity.
Authors: Luciana Werneck Zuccherato, Renan Pedra Souza, Ricardo Mesquita Camelo, Márcio Antônio Portugal Santana, Maíse Moreira Dias, Letícia Lemos Jardim, Andrea Gonçalves de Oliveira, Claudia Santos Lorenzato, Monica Hermida Cerqueira, Vivian Karla Brognoli Franco, Rosangela de Albuquerque Ribeiro, Leina Yukari Etto, Maria do Rosario Ferraz Roberti, Fábia Michelle Rodrigues de Araújo Callado, Maria Aline Ferreira de Cerqueira, Ieda Solange de Souza Pinto, Andrea Aparecida Garcia, Tania Hissa Anegawa, Daniele Campos Fontes Neves, Daniel Gonçalves Chaves, Suely Meireles Rezende
Institutions: Universidade Federal de Minas Gerais, California State University, Northridge, Fundação Oswaldo Cruz, Fundação Centro de Hematologia e Hemoterapia de Minas Gerais, Hemorio, Universidade Federal do Ceará, Universidade Federal da Paraíba, Fundação Pró-Sangue Hemocentro de São Paulo, Universidade Federal de Goiás, Fundação Hemopa, Universidade Federal do Pará, Faculdade de Medicina de São José do Rio Preto, Universidade Estadual de Londrina, Universidade Federal de Rondônia
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,250
OpenAlex ID: W4413149194