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Analysis of the Genotypes and Phenotypes of 37 Unrelated Patients with Inherited Factor VII Deficiency

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Analysis of the Genotypes and Phenotypes of 37 Unrelated Patients with Inherited Factor VII Deficiency European Journal of Human Genetics (2001) 9, 105 ± 112 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency Muriel Giansily-Blaizot*,1, Patricia Aguilar-Martinez1, Christine Biron-Andreani1, Philippe Jeanjean1,HeÂleÁne Igual1, Jean-FrancËois Schved1 and The Study Group of Factor Seven Deficiency2 1Laboratory of Haematology, CHU Montpellier, University Hospital, Montpellier, France Severe inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder with a poor relationship between FVII coagulant activity and bleeding tendency. Both clinical expression and mutational spectrum are highly variable. We have screened for mutations the FVII gene of 37 unrelated patients with a FVII coagulant activity less than 5% of normal pooled plasmas. The nine exons with boundaries and the 5' flanking region of the FVII gene were explored using a combination of denaturing gradient gel electrophoresis and direct DNA sequencing. This strategy allowed us to characterise 68 out of the 74 predicted FVII mutated alleles. They corresponded to a large panel of 40 different mutations. Among these, 18 were not already reported. Genotypes of the severely affected patients comprised, on both alleles, deleterious mutations which appeared to be related to a total absence of activated FVII. We suggest that this absence of functional FVII can explain the severe clinical expression. Whether a small release of FVII is sufficient to initiate the coagulation cascade and to prevent the expression of a severe phenotype, requires further investigations. European Journal of Human Genetics (2001) 9, 105 ± 112. Keywords: factor VII deficiency; haemorrhagic disorder; single base-pair mutation Introduction domains and a C-terminal serine proteinase domain. After Human coagulation factor VII (FVII) is a vitamin-K-depen- cleavage of an Arg-Ile peptide bond at residues 152/153, FVII dent glycoprotein that consists of a 406 amino-acid modular is converted to the active form, factor VIIa (FVIIa) comprising protein with a N-terminal-gamma-carboxyglutamic acid rich two chains connected by a disulphide bridge between Cys (Gla) domain, two epidermal growth factor-like (EGF) 135 and Cys 262. FVIIa on its own has virtually no catalytic activity but triggers the coagulation at sites of injury by binding to the cell surface receptor tissue factor (TF) in the *Correspondence: M Giansily-Blaizot, Laboratory of Haematology, CHU presence of calcium ions, ultimately resulting in thrombin 1 Montpellier, 80 avenue Augustin Fliche, 34 295 Montpellier Cedex 5, generation and the formation of a fibrin clot. France. Tel: +33 4 67 33 70 33; Fax: +33 4 67 33 70 36; Inherited FVII deficiency is a rare autosomal recessive E-mail: [email protected] disorder with an estimated incidence of 1 in 500 000. The 2The study group of factor seven deficency includes: MA Bertrand CHU BesancËon, Dr JY Borg CHU Rouen, Dr ME Briquel CHU Nancy, bleeding tendency in affected patients is highly variable and Dr H Chambost CHU Marseille, Dr F Dutrillaux CHU Dijon, Dr R Favier correlates poorly with plasma FVII activity levels.2 The AP-HP Paris, Dr V Gay Dr D Raffenot CHG Chambery, Pr J Goudemand clinical features vary considerably, from easy bruising, CHU Lille, Dr R Navarro CHU Montpellier, Dr C Negrier Dr A Durin epistaxis, modest or severe postoperative bleeding, to life- CHU Lyon, Dr R d'Oiron CTH BiceÃtre Paris, Dr A Parquet Gernez ETS Lille, 1±3 Dr G Pernod CHU Grenoble, Dr J Peynet Dr B Bastenaire CTH Le threatening intracranial haemorrhages. On the other Chenay Paris, Pr P Sie CHU Toulouse, Dr N Stieltjes CTH Cochin Paris, hand, several asymptomatic patients with a FVII coagulant Dr MF Torchet Dr C Gazengel ETS AP-HP Paris (France), Pr P de activity level less than 1% of normal have been reported.1 In Moerloose CHU Geneve (Switzerland). Received 11 July 2000; revised 22 September 2000; accepted addition, up to 70 different mutations underlying the FVII 29 September 2000 deficiency phenotype have already been described in the Molecular heterogeneity of FVII deficiency M Giansily-Blaizot et al 106 human FVII mutation database (http://europium.csc.mrc. simulation of the melting behaviour of any DNA sequence, ac.uk/usr). Study of the heterogeneous molecular basis of were used to optimise the DGGE conditions. To ensure FVII deficiency offers the opportunity to investigate the that the DNA portion of interest was within the lowest mechanisms through which genotype is able to modulate the melting temperature domain, a GC rich region was added residual FVII activity and to produce a large spectrum of at one end of the fragment to be screened as described.8 clinical phenotypes. For this purpose, we have collected As the melting map of exons 1a, 2, 3, 4, 6 and 7 did not clinical features and characterised the FVII genotypes of a easily allow the use of DGGE, these PCR fragments were large cohort of patients displaying FVII coagulant activity less directly sequenced. DGGE was performed for the mutation than 5% of normal pool plasmas. This study is one of the screening of exons 1b, 5 and 8. Three sets of primers were largest ever reported on severe FVII deficiency.4±6 used to independently amplify the three melting domains of exon 8, generating fragments 8A, 8B and 8C. Migration gels consisted of 6.5% acrylamide in a linear 50 ± 90% Materials and methods denaturing gradient and were run as previously described9 Patients (Table 2). Samples displaying abnormal DGGE profiles were The panel consisted of 37 unrelated patients (22 females and sequenced. 15 males) with inherited FVII deficiency attending 16 French centres specialising in the follow-up of haemorrhagic Mutation detection by direct sequencing disorders. Patients who entered the study were selected on PCR amplified fragments for coding regions 1a, 2, 3, 4, 6, 7, the basis of a factor VII coagulant activity level less than 5% exon-intron boundaries, 5'FR and samples with an abnormal of normal (Table 1). All patients gave written informed DGGE pattern were directly sequenced using the Big dye consent in accordance with the French law. A family history Terminator sequencing kit (Perkin Elmer, Norwalk, CT, USA) of consanguinity was known for six patients. on an Applied 310 sequencing apparatus (PE, Applied Biosystems,Warrington, UK). Clinical and biological data Clinical features were recorded by the physician in charge of Mutation screening strategy each patient in a standardised questionnaire. Collected data In this study, we have made an exhaustive genetic analysis focused on the diagnostic circumstances and on the bleeding of all FVII regions of interest so as not to miss double- tendency. The type, severity and frequency of the haemor- mutations or polymorphisms that could be involved in the rhagic symptoms were noted. The FVII coagulant activity phenotypic variability. For each patient, the sequences of (FVIIc) was assayed in each centre by a one-stage method the nine exons and corresponding boundaries of FVII gene based on the prothrombin time using thromboplastin were analysed. Each nucleotide sequence alteration was reagents and FVII deficient plasma as a substrate. Factor VII confirmed on at least two independent PCR products by antigen (FVIIAg) was determined using the Asserachrom either restriction enzyme digestion, when the mutation FVII:Ag Kit (Diagnostica Stago, Asniere, France) according to modified a restriction site, or another independent the manufacturer's instructions (Table 1). sequencing analysis. If no mutation was found after the first screening-step, exons 1b, 5 and 8 were tested for Blood collection heteroduplex formation under the same DGGE conditions, Blood samples were obtained from the 16 centres and mailed and the 5'FR was sequenced. If one or two mutations were to the laboratory at room temperature within 24 h, for DNA still missing, exons 1b, 5 and 8 were then entirely extraction. sequenced. DNA isolation and conditions for polymerase chain reaction Results Genomic DNA was isolated according to standard methods. Clinical and biological phenotypes The coding portions, intron/exon boundaries and the 5' The 37 patients investigated in this study were classified flanking region (5'FR) of the FVII gene were amplified from into three clinical groups (Table 1). Group A comprised genomic DNA by polymerase chain reaction (PCR). Primer asymptomatic patients with no bleeding history (n=15). sets were designed according to the published FVII gene Group B included patients who experienced menorrhagia, sequence7 and are listed in Table 2. epistaxis or bruising with no need for substitutive therapy (n=13). Group C comprised patients with a history of Mutation detection by denaturing gradient gel severe bleeding (haematoma, haemarthrosis, intracranial electrophoresis (DGGE) haemorrhages) (n=9). The severe disease group comprised DGGE was used to screen for sequence alterations, PCR only females, whereas the mild disease groups included 15 fragments containing the portions of interest of FVII gene. males and 13 females. No thromboembolic episode was MELT 87 and SQHTX computer programs,8 which allow related. European Journal of Human Genetics Molecular heterogeneity of FVII deficiency M Giansily-Blaizot et al 107 Table 1 Identified phenotypes and genotypes of the 37 FVII deficient patients Non French Clinical Biological phenotypes (%) Genotypes and haplotypes Lab number Sex
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