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

Table 2 Mutational spectrum of hemophilia A (F8 variants) and associated phenotypes

Mutation type	Approximate distribution	Associated severity	Molecular mechanism
Inv22[15-20]	40%-50% of severe HA globally; lower in some regions (e.g., 10.5% in Albania, approximately 30% in parts of India/Asia)	Severe	Homologous recombination between int22h-1 and extragenic int22h-2/int22h-3 repeats - disrupted F8 transcription
Inv1[15-17]	2%-5% of severe HA	Severe	Homologous recombination within intron 1
Nonsense mutations[14]	Common among severe, inversion-negative HA	Severe	Premature stop codons - truncated nonfunctional FVIII; often triggers NMD
Frameshift mutations (small insertions/deletions)[17-19]	Frequent in severe HA; multiple novel variants identified in several populations	Severe	Reading-frame disruption - premature truncation
Canonical splice-site mutations[14,17]	Common among severe phenotypes	Severe	Aberrant splicing - exon skipping or truncation
Missense mutations[16,17,22]	Predominant in mild and moderate A; smaller contribution to severe HA (especially at conserved residues)	Mild-moderate; occasionally severe	Residue substitution affects FVIII structure, stability, or cofactor function
Small deletions/insertions (non-frameshift)[22]	Less common but clinically significant	Mild-severe depending on domain affected	Disruption of local protein domains without full truncation
Large deletions/multiexon deletions[21]	Rare	Severe	Loss of entire domains - absent FVIII
Composite (double) mutations[18]	Rare	Severe	Combined effects of two pathogenic variants

HA: Haemophilia A; Inv22: Intron 22 inversion; Inv1: Intron 1 inversion; NMD: Nonsense mutational deletions.