Molecular pathogenesis and therapeutic advances in haemophilia, an update of the current evidence

Table 3 Mutational spectrum of haemophilia B (F9 variants) and structural consequences

Mutation type	Approximate distribution	Associated severity	Structural mechanism
Missense variants[11,23-25]	Approximately 68% of all F9 variants; the dominant mutation class[11]	Mild-moderate most commonly; sometimes severe when essential residues affected	Alter FIX folding, γ-carboxylation, calcium binding, catalytic triad stability, or activation peptide processing
Nonsense mutations[25,28]	Less common than missense; significant proportion in severe HB	Severe	Premature truncation - absent or unstable FIX protein; NMD frequently triggered
Frameshift variants (insertions/deletions)[25]	Relatively uncommon but clinically important	Severe	Frameshift - truncated nonfunctional protein
Canonical splice-site mutations[25,28]	Common among severe HB due to compact exon-domain architecture	Severe	Aberrant splicing - exon skipping, truncated proteins, or defective post-translational processing
Promoter mutations (including HB Leyden)[11]	Rare overall	Childhood severe - spontaneous improvement after puberty	Androgen-responsive elements regulate transcription; puberty FIX expression
Synonymous pathogenic variants[27]	Rare but increasingly recognized	Mild-severe depending on impact on mRNA	Alter mRNA structure, translation rate, and co-translational folding (e.g., p.Val107Val)
Large deletions (partial or whole-gene)[29]	1%-3% of F9 mutations	Severe	Loss of entire exons or full gene; often destabilizes neighboring genomic regions
Contiguous gene deletion syndromes[29]	Extremely rare	Severe haemophilia + syndromic features	Deletion of F9 plus adjacent genes - multi-system phenotype

HB: Haemophilia B; NMD: Nonsense mutational deletions.