Two novel factor V null mutations associated with activated protein C resistance phenotype/genotype discrepancy

Area of Science:

• Hematology
• Molecular Genetics
• Clinical Diagnostics

Background:

• Activated protein C (APC) resistance is a common inherited thrombophilia, typically associated with the factor V Leiden mutation.
• Phenotypic assays measure APC resistance, while genotypic assays detect specific mutations in the factor V gene.
• Discrepancies between APC resistance phenotype and genotype are exceptionally rare, posing diagnostic challenges.

Observation:

• Two cases presented with a discrepancy between their measured APC resistance phenotype and their known factor V Leiden genotype.
• Detailed molecular analysis involved direct sequencing of the factor V gene, including all exons and splicing junctions.

Findings:

• The observed phenotype/genotype discrepancy was attributed to the presence of two previously unidentified factor V null mutations.
• These novel null mutations, in conjunction with a heterozygous factor V Leiden mutation, altered the functional expression of factor V, leading to the resistance phenotype.
• This combination of mutations explains the unusual clinical presentation.

Implications:

• The findings underscore the importance of considering molecular mechanisms beyond the common factor V Leiden mutation in cases of unexplained APC resistance.
• Accurate diagnosis requires a comprehensive approach, integrating both phenotypic and genotypic analyses, especially in rare discrepant cases.
• This study contributes to a deeper understanding of factor V gene mutations and their impact on thrombotic risk assessment.