What is the hereditary pattern of Hemophilia A?

Hereditary Pattern of Hemophilia A

Hemophilia A is an X-linked recessive congenital bleeding disorder that primarily affects males due to their single X chromosome, while females typically serve as carriers of the disease 1.

Genetic Basis and Inheritance

• Hemophilia A results from deficiency of functional coagulation factor VIII (FVIII), which is encoded by the F8 gene located on the X chromosome 1, 2
• Most individuals with hemophilia A have a pathogenic variant in the F8 gene 1
• As an X-linked recessive disorder, males who inherit the mutated F8 gene will develop hemophilia A, while females with one mutated copy typically become carriers 2
• The estimated prevalence of hemophilia A at birth is 24.6 cases per 100,000 males, accounting for approximately 80-85% of all hemophilia cases 1
• For every 100 males with hemophilia, there are approximately 277 potential carriers 2

Disease Manifestation in Males

• Males with hemophilia A express the full disease phenotype due to having only one X chromosome 3
• Severity is classified based on factor VIII activity levels 4:
  • Severe: <1% of normal factor VIII activity
  • Moderate: 1-5% of normal factor VIII activity
  • Mild: >5% to <40% of normal factor VIII activity

Female Carriers

• Females who inherit one mutated F8 gene typically become asymptomatic carriers due to the presence of a second, normal X chromosome 3, 2
• Female carriers usually have factor VIII levels around 50% of normal, which is generally sufficient to prevent bleeding symptoms 3
• Carrier detection has evolved from phenotypic studies based on coagulation tests to highly precise genetic analysis using next-generation sequencing 5
• Single nucleotide polymorphism (SNP) and microsatellite markers can be used for successful identification of carriers in affected families 6

Rare Cases of Symptomatic Female Carriers

• In rare instances, female carriers may manifest symptoms of hemophilia A due to skewed X-chromosome inactivation (lionization) 3, 7, 5
• Skewed X-chromosome inactivation occurs when more normal X chromosomes are converted to Barr bodies, leaving more abnormal chromosomes active in body cells 3
• The severity of manifestations in symptomatic female carriers is directly proportional to the level of clotting factor in the blood 3
• Symptomatic female carriers may require the same treatment approaches as affected males 3

Genetic Testing and Counseling

• Molecular characterization of hemophilia A may involve:
  • Detection of intron 22 inversion (a common mutation in severe hemophilia A) 7
  • Multiplex ligation-dependent probe amplification to detect large deletions 7
  • Analysis of X-chromosome inactivation status 7, 5
• Genetic counseling is essential for families affected by hemophilia A, especially for carrier females planning pregnancies 5
• Prenatal diagnosis options have evolved from examination of FVIII levels in fetal blood samples to genetic analysis of fetal DNA from chorionic villus sampling 5
• In some countries, in vitro fertilization combined with preimplantation genetic diagnosis has become the procedure of choice for carriers wishing to prevent transmission of hemophilia A 5

Clinical Implications

• Understanding the X-linked inheritance pattern is crucial for:
  • Accurate genetic counseling of affected families 5
  • Identifying at-risk female carriers 5, 6
  • Prenatal diagnosis and family planning 5
  • Appropriate clinical management of both affected males and symptomatic female carriers 3