Severe Congenital Factor VII Deficiency Without Molecular Diagnosis: The Case for Comprehensive Genomic Analysis

Abstract

Introduction: Congenital Factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder typically caused by pathogenic variants in the F7 gene. However, some patients with severe biochemical deficiency and significant bleeding lack identifiable mutations. We describe three such cases, highlighting the need for broader genomic analysisto elucidate the underlying mechanisms. Method(s): Three unrelated patients with severe FVII deficiency (FVII:C =4 in adult males, >=6 in adult females) were assessed at a tertiary haemophilia centre. Phenotypic evaluation included bleeding history and FVII activity measurement. Genetic analysisinvolved full F7 gene sequencing (exons and exon-intron boundaries) and multiplex ligation-dependent probe amplification (MLPA) to assess for large deletions or duplications. Variant interpretation followed ACMG/AMP guidelines. Result(s): All three patients exhibited recurrent mucocutaneous bleeding, and the affected females additionally experienced heavy menstrual bleeding, consistent with a severe phenotype. FVII activity was markedly reduced, but no pathogenic or likely pathogenic variants were detected in F7. MLPA demonstrated a normal copy number across all exons. Discussion/Conclusion: This series highlights patients with clinically and biochemically severe FVII deficiency in whom no causative F7 variant or structural abnormality was found. These findings expose a diagnostic gap in rare bleeding disorders and underline the limitations of current sequencing strategies. Whole genome sequencing (WGS) may reveal novel non-coding, regulatory, or deep intronic variants influencing F7 expression. Broader genomic exploration is crucial to improve diagnosis and understanding of FVII pathophysiology.