Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency

Abstract

Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series.

A novel gene insertion combined with a missense mutation causing factor VII deficiency in two unrelated Chinese families

“…However, the sequence of 3 0 untranslated region of F7, which is important to posttranscriptional regulation through controlling the stability or translational efficiency of mRNA [12], was affected indirectly. In addition, a disulfide bridge (Cys-340-Cys-368) disappeared because of the mutation, which exhibited a high conservation in the vitamin-K-dependent coagulation factors and plays a vital part in stabilizing the protein conformation [4]. Thereby, we speculate that g.11520-11521insT may destabilize the conformation of the catalytic domain and result in abnormal mRNA generation.…”

“…Synthesized by the liver, FVII is one of the vitamin K-dependent glycoproteins with 406 amino acids, consisting of certain scattered significant domains, followed by the Gla domain, two epidermal-like growth factor domains, and the catalytic domain [1][2][3]. Inherited FVII deficiency is defined as a rare autosomal recessive disorder with prevalence of about 1 : 500 000 [4], which may increase if somewhere consanguineous marriage happens [5]. Furthermore, there is no clear correlation between FVII levels and the clinical manifestations, which are known to be affected by genetic mutation, polymorphism, and other factors, such as sex, age, and physical condition [6,7].…”

Rare Bleeding Disorders are not so Rare in Pakistan

“…In patients with FVII deficiency, 13 had levels <5%, 3 patients had levels >5-10% and 2 patients had >10-30%. Thus its severity was graded as per the clinical presentation [8,9]. All patients with fibrinogen deficiency were diagnosed with afibrinogenaemia (less than 20mg/dl).…”

Expanded carrier screening and preimplantation genetic diagnosis in a couple who delivered a baby affected with congenital factor VII deficiency

“…Congenital FVII deficiency and cystic fibrosis are life-threatening diseases. Congenital FVII deficiency caused by mutations in the F7 gene is characterized by varying degrees of bleeding and is associated with easy bruising, recurrent epistaxis, menorrhagia, haemarthrosis, and intracranial haemorrhage [ 18 , 19 ]. Cystic fibrosis is caused by mutations in the CFTR gene with manifestations of pancreatic insufficiency, pulmonary abnormalities such as recurrent and chronic bronchopulmonary infections, bronchiectasis, and chronic obstructive pulmonary disease, and congenital bilateral absence of the vas deferens (CBAVD), which causes male infertility [ 20 , 21 ].…”