Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Zhang, Xiaoyu; Wang, Shuwen; Leng, Shaoqiu; Feng, Qi; Zhang, Yanqi; Xu, Shang‐Fu; Zhang, Xinsheng; Fang, Yunhai; Peng, Jun; Sheng, Zi

doi:10.1002/jcla.23905

Cited by 3 publications

(5 citation statements)

References 33 publications

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“…In 2021, Zhang et al detected four novel variations (c.251T>C, c.466G>A, c.1016C>T, c.-16T>G) and investigated their pathogenicity using PyMOL2.4, Swiss-PDB Viewer, SIFT, POLYPHEN-2. Bioinformatics analyses found these variations pathogenic (49). In another study, Liang et al detected two novel variations in three patients with FVII deficiency; the molecular model analysis of the two novel mutations (Cys115Arg and Pro324Leu) indicated impairment of the proper folding of the EGF1 domain and impairment of the F7 coagulant activity (50).…”

Section: F7 Gene Variationsmentioning

confidence: 99%

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Mashayekhi

Ghasemi

2022

Trends in Med Sci

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: Coagulation factor VII (FVII) is a vitamin K-dependent serine protease that plays a pivotal role in normal hemostasis. Mature FVII is a glycoprotein comprised γ-carboxyglutamic acid-rich (Gla) domain, two epidermal growth factor (EGF)-like domains, an activation domain, and a serine protease domain. FVII requires proteolytic activation followed by tissue factor (TF) binding for maximal activity. The F7 gene (14.8 kb) is located on 13q34, composed of nine exons and eight introns. The congenital FVII deficiency is a rare coagulopathy with an autosomal recessive pattern of inheritance that occurs due to mutation in the F7 gene. A considerable number of mutations of different types have been identified throughout this gene affecting the expression, structure, and post-translational alterations of the protein. FVII deficiency is the most frequently recessively inherited bleeding disorder. Subjects with FVII deficiency show a wide range of symptoms, including cutaneous hemorrhage, mucosal hemorrhage, gastrointestinal bleeding, joint bleeding, and central nervous system (CNS) hemorrhage. Unlike other coagulation factor deficiencies, serum levels of FVII do not demonstrate the severity of the disease, and there is no direct correlation between serum levels and clinical complications. Replacement therapy is the treatment of choice for FVII deficiency. Various therapeutic products such as prothrombin complex concentrate, plasma-derived FVII concentrate, fresh frozen plasma, and activated recombinant FVII are available to treat FVII deficient individuals. This review aims to provide information on molecular, biochemical, and clinical aspects of coagulation FVII, its role in hemostasis, and the consequences of its deficiency.

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Section: F7 Gene Variationsmentioning

confidence: 99%

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Mashayekhi

Ghasemi

2022

Trends in Med Sci

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“…A complete blood count showed a white cell count of 2.9 × 10 9 /L, a hemoglobin level of 83 g/L and a platelet count of 212 × 10 9 /L. Routine coagulation tests showed that the prothrombin time (PT) was markedly elevated (35.0 s, normal range 10-14 s); the international normalized ratio (INR) was 2.92 (normal range [10][11][12][13][14]; the FVII activity level was extremely low at 2.1% of normal on a Siemens automatic blood coagulation analyzer (Siemens 5100); and the activated partial thromboplastin time (APTT), thrombin time (TT) and D-dimer were within their respective reference ranges. The FVII:Ag was checked with an enzyme-linked immunosorbent assay (ELISA) kit (Changfeng), the phenotypes of this family are shown in Table 1, and the pedigree is shown in Figure 1.…”

Section: A S E Pr E S E Ntati O Nmentioning

confidence: 99%

“…9 Phe84Ser and p.Gly156Cys affected the Gla and EGF domains of FVII, respectively, causing hereditary coagulation factor VII deficiency. 10 Here, we report a pedigree of congenital FVII deficiency, the proband was a 30-year-old female with severely low FVII activity who was subsequently diagnosed with congenital compound heterozygous FVII deficiency. The clinical manifestations and laboratory results of the proband and her family members are presented, the genetic analysis of the proband was performed by secondgeneration sequencing, and the bioinformatics and amino acid homology analyses were conducted.…”

Section: Introductionmentioning

confidence: 99%

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Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations in a Chinese pedigree: A case report

Cai

et al. 2022

Clinical Laboratory Analysis

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Background Congenital coagulation factor VII (FVII) deficiency is a rare, autosomal‐recessive haemorrhagic disorder with an estimated incidence of 1:500,000. This disorder is caused by mutations in the F7 gene. Case description Here, we report a pedigree of congenital FVII deficiency. The proband was a 30‐year‐old female with severely low FVII activity and a history of menorrhagia and epistaxis since her childhood who was subsequently diagnosed with congenital compound heterozygous FVII deficiency. A genetic study revealed a novel combination of compound heterozygous mutations (c.64G 〉 A, p.Gly22Ser and c.1027G 〉 A, p.Gly343Ser). Her father and older son had the c.64G 〉 A, p.Gly22Ser (heterozygous) mutation. Her mother and younger son had the c.1027G 〉 A, p.Gly343Ser (heterozygous) mutation. The predicted results of PolyPhen‐2 and MutationTaster indicated that these mutations were probably damaging and disease‐causing, respectively. Conclusion In this study, we identified a novel combination of genetic mutations that could expand the mutant library and help in elucidating the pathogenesis of hereditary human coagulation FVII deficiency. A novel combination of compound heterozygous mutations was reported for the first time in Chinese individuals.

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“…Whereas FVII:C shows a poor correlation to severity of bleeding phenotype the type and the site of a F7 variant may be helpful to predict hemorrhagic risks (13). For example, mutations affecting TFPI-binding exosites of FVII may markedly prolong clotting time (14).…”

Section: Introductionmentioning

confidence: 99%

Utility of ACMG classification to support interpretation of molecular genetic test results in patients with factor VII deficiency

Alesci¹,

Hecking²,

Racké³

et al. 2023

Front. Med.

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BackgroundThe American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have introduced an internationally shared framework for variant classification in genetic disorders. FVII deficiency is a rare inherited autosomal recessive bleeding disorder with sparse data concerning ACMG classification.MethodsTo develop an approach which may improve the utility of molecular genetic test results, 129 patients with FVII deficiency were retrospectively assigned to six subgroups for exploratory analysis: F7 gene wildtype (group 1), ACMG 1 (benign variant) or ACMG 2 (likely benign variant), only (group 2), ACMG 3 (variant of uncertain significance) ± ACMG 1–2 heterozygous or not classified variant (group 3), ACMG 4 (likely pathogenic variant), or ACMG 5 (pathogenic variant) single heterozygous ± ACMG 1–3 single heterozygous (group 4), ACMG 4–5 homozygous or ≥2 ACMG 4–5 heterozygous or ≥1 ACMG 4–5 heterozygous plus either ACMG 1 c.1238G>A modifying variant homozygous or ≥2 ACMG 1–3 (group 5), FVII deficiency and another bleeding disorder (group 6).ResultsEleven of 31 patients (35.5%) in group 5 had abnormal ISTH-BS (n = 7) and/or history of substitution with recombinant factor VIIa (n = 5) versus 4 of 80 patients (5.0%, n = 1 abnormal ISTH-BS, n = 3 substitution) in groups 1 (n = 2/22), 2 (n = 1/29), 3 (n = 0/9), and 4 (n = 1/20). Four of 18 patients (22.2%) with FVII deficiency and another bleeding disorder (group 6) had an abnormal ISTH-BS (n = 2) and/or history of substitution with recombinant factor VIIa (n = 3).ConclusionPatients with a homozygous ACMG 4–5 variant or with specific combinations of heterozygous ACMG 4–5 ± ACMG 1–3 variants exhibited a high-risk bleeding phenotype in contrast to the remaining patients without another bleeding disorder. This result may serve as a basis to develop a genotype/phenotype prediction model in future studies.

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Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency

Cited by 3 publications

References 33 publications

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Coagulation Factor VII: Genetic, Molecular, and Clinical Characteristics

Hereditary coagulation factor VII deficiency caused by novel compound heterozygous mutations in a Chinese pedigree: A case report

Utility of ACMG classification to support interpretation of molecular genetic test results in patients with factor VII deficiency

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