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

Shirin Ravanbod; Mohammad Faranoush; Majid Changi-Ashtiani; Hassan Rokni-Zadeh; Tina Shahani

doi:10.1016/j.rpth.2022.100003

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

Res Pract Thromb Haemost. 2022 Nov 26;7(1):100003. doi: 10.1016/j.rpth.2022.100003. eCollection 2023 Jan.

Authors

Shirin Ravanbod¹, Mohammad Faranoush^{1

2}, Majid Changi-Ashtiani³, Hassan Rokni-Zadeh^{4

5}, Tina Shahani^{4

6}

Affiliations

¹ Molecular Genetics Laboratory, Iranian Hemophilia and Thrombophilia Association (MAHTA), Tehran, Iran.
² Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran 1449614535, Iran.
³ School of Mathematics, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
⁴ Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran.
⁵ Department of Medical Biotechnology, School of Medicine, Zanjan University, of Medical Sciences, Zanjan, Iran.
⁶ Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran.

Abstract

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.

Keywords: Exome sequencing; FVII inhibitor; FVII phenotype; bleeding; coagulation Factor VII; founder effect; intracranial hemorrhage; novel mutation.