Extensive genetic screening of Iranian Factor FVII-deficient individuals unraveled several novel mutations and postulated founder effects in some cases

BACKGROUND: As the most frequent congenital rare bleeding disorder that transmits in an autosomal recessive manner, factor VII (FVII) deficiency is a serious bleeding complication in populations with high rate of in-marriages. While diagnosis mainly relies on clinical and laboratory phenotypes, plasma FVII antigen and activity levels do not often correlate with symptoms’ severity. OBJECTIVES: Genetic profiling of the affected individuals potentially improves our biological understanding of this complicated rare disorder. METHODS: Conventional polymerase chain reaction-Sanger sequencing and whole-exome sequencing were applied for genetic profiling of F7 gene in 66 symptomatic FVII-deficient individuals from 62 independent pedigrees. Thirty-nine asymptomatic relatives of the patients were also studied. RESULTS: Thirty different F7 pathogenic variations were identified in the studied cases of which 11 have not been reported before. The novel mutations include 5 missenses (c.715G>A, c.794T>C, c.1090C>G, c.1222C>A, c.1265T>C), 3 splicing (c.316+1G>T, c.682-2A>G, c.572-16C>G), 2 nonsenses (c.790delC, c.1248G>A), and 1 frameshift (c.1346delA). A founder effect is proposed for c.790delC that was detected in 8 independent pedigrees who were all from similar geographical regions and ethnic backgrounds. Homozygous c.790delC reduces plasma FVII activity to <1% and causes spontaneous intracranial hemorrhage in early infancy. CONCLUSION: From the 66 studied symptomatic FVII-deficient individuals, 58 were homozygous carriers of the identified variations. Identification of homozygotes clarifies the potential role of nucleotide variations in reducing FVII activity and their contributions to a certain phenotype. Some of those variations, such as c.1A>G, c.509G>A, c.634C>T, and c.1285G>A have only been previously reported as heterozygous.