F8 pathogenic variants identified in the HA carrier cohort. In the GIDEHAC cohort (N = 361 HA carriers), 164 different pathogenic variants of the F8 gene were identified. Null and non-null variants were predicted to have a major and a mild deleterious effect on FVIII synthesis, respectively. The null variant group included inversions of introns 1 and 22, nonsense variants, large deletions or duplications, and small insertions/deletions creating a frameshift with a predicted premature stop codon. The latter included small insertions/deletions located in polyA runs, although some of these could be associated with an in-frame nucleotide repositioning mechanism, allowing only low FVIII synthesis and therefore moderate HA. The non-null variant group included missense variants, intron anomalies (nucleotides substitutions or deletions/insertions distant from exons), and nucleotide substitutions located in the promoter.