KUMJ | VOL. 24 | NO. 2 | ISSUE 95 | APRIL - JUNE, 2026

Genetics of Hemophilia
Khanal PR, Kulshrestha H, Thakur N

Abstract:
Hemophilia A (HA) is an X-linked bleeding disorder caused by heterogeneous pathogenic variants in the factor VIII gene (F8), located at Xq28, with an estimated incidence of 1 in 5,000–10,000 males. The molecular basis of HA is highly diverse, encompassing point variants, deletions, insertions, and structural rearrangements, with intron 22 and intron 1 inversions accounting for the majority of severe cases. A strong genotype–phenotype correlation exists, making molecular characterization essential for accurate diagnosis, prognosis, and management. This review examines the molecular basis of HA, including F8 gene structure and variant spectrum, patterns of inheritance (including rare symptomatic “hemophilic females”), and the evolution of genetic testing strategies - from Southern blotting and Sanger sequencing to next-generation sequencing (NGS). To review the molecular basis of HA, highlight the associations of genotype– phenotype and, molecular (genetic) testing relics the definitive diagnostic tool for HA. Literature on F8 gene structure, mutation spectrum, inheritance patterns, and diagnostic approaches was examined with emphasis on intron 22 and intron 1 inversions, which account for most severe cases. Analyzed the modern advanced techniques for the diagnosis and highlighted with target on intron 22 and intron 1 inversions. HA demonstrates heterogeneous genetic mechanisms, including point mutations, deletions, insertions, and structural rearrangements. Strong genotype–phenotype correlations make molecular characterization essential for accurate diagnosis, prognosis, and management. Next-generation sequencing has significantly improved mutation detection rates, reduced turnaround time and cost, and enhanced understanding of inhibitor risk and reproductive options. However, a small proportion of cases remain molecularly unexplained. HA is considered a genetic disease so the diagnosis of HA with the advanced techniques is critical for Genetic counseling, reproduction, profession and tragedies. Knowledge and preventive measures are the key factors for planning and policy.
Keyword : Factor VIII (F8) gene, Genetic counseling, Hemophilia A, Intron 22 inversion, Nextgeneration sequencing, Prenatal diagnosis