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Introduction: Advances in genomic sequencing have facilitated the sequencing of genes associated with disorders of haemostasis. The identification of variants within genes and access to curated data incorporating structural, functional, evolutionary as well as phenotypic data has become increasingly important in order to ascribe pathogenicity. Aim: The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Database Project aims to provide a single port of entry to a web‐accessible resource for variants in genes involved in clinical bleeding disorders. Results: New databases have evolved from previously developed single gene variant coagulation database projects, incorporating new data, new analysis tools and a new common database architecture with new interfaces and filters. These new databases currently present information about the genotype, phenotype (laboratory and clinical) and structural and functional effects of variants described in the genes of factor (F) VII (F7), FVIII (F8), FIX (F9) and von Willebrand factor (VWF). Conclusion: The project has improved the quality and quantity of information available to the haemostasis research and clinical communities, thereby enabling accurate classification of disease severity in order to make assessments of likely pathogenicity. [ABSTRACT FROM AUTHOR]

The article presents a study which reported eight unrelated patients from Pakistan suffering from congenital factor V (FV) deficiency. Topics discussed include the severity of bleeding symptoms of the patients, the lack of correlation found between the clinical expression of the disease and genetic defects, and implication of the paradox between the expected pathogenicity of frameshift mutations and the relatively mild clinical phenotype of the patients.

Abstract: Severe iron overload is frequent in dehydrated hereditary stomatocytosis (DHSt) despite well‐compensated hemolysis and no or little transfusion requirement. We investigated 4 patients with proven DHSt, in whom the degree of hemolysis was closely related to iron status. Genetic modifiers increasing iron stores (HFE:pCys282Tyr, HAMP:c‐153C>T mutations) were accompanied with high liver iron concentrations and increased hemolysis, whereas therapeutic phlebotomies alleviated the hemolytic phenotype. There were no manifestations of hemolysis in one patient with low iron stores. Hemolysis reappeared when iron supplementation was given. The search for genetic or acquired modifiers of iron status and the modulation of iron stores may help in the management of these patients. [ABSTRACT FROM AUTHOR]

Background & Aims Iron overload ( IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma ( HCC). Methods Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 μg/L (males) or ≥200 μg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration ( LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO ( HFE, HJV/ HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. Results A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 μmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. Conclusions Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives. [ABSTRACT FROM AUTHOR]

The article focuses on importance of prenatal diagnosis and primary prophylaxis in preventing Congenital factor VII (FVII) autosomal recessive haemorrhagic disorder. It states that variability exists in Clinical phenotypes of FVII disorder such as central nervous system (CNS) and/or gastrointestinal (GI) tract bleeding and mentions that in prenatal diagnosis of FVII disorder, amniocentesis is performed between 16 and 19 weeks of pregnancy.

Inherited factor VII (FVII) deficiency is a rare autosomal recessive bleeding disorder mostly caused by point mutations. Large genomic re-arrangements at F7 locus could account for a fraction of mutant alleles that remain unidentified after DNA sequencing, because they escape conventional polymerase chain reaction (PCR)-based techniques. We report the first systematic screening of F7 for large re-arrangements, by semi-quantitative multiplex PCR of fluorescent fragments targeting the 9 exons and the promoter region. A well-characterised cohort of 43 unrelated patients either apparently homozygous for a F7 point mutation or carrying at least one unidentified F7 mutant allele participated in this study. Two large F7 re-arrangements were identified in two FVII-deficient pedigrees, including a discontinuous deletion involving two distinct portions of F7 whose proximal and distal end junctions were characterised. A simple and efficient method for the routine detection of gross alterations of F7, which accounted for 2.3% of mutant alleles in our sample, is now available in inherited FVII deficiency. This test should complement conventional PCR-based techniques not only in unsolved cases, but also where inheritance pattern analysis is not achievable. [ABSTRACT FROM AUTHOR]

Emphasizes the reliability of detection assay and linkage analysis in the diagnosis of severe inherited blood coagulation factor VII (FVII) deficiency. Information on the case of a two-year-old girl with FVII; Overview of prenatal mutation screening; Description of mutation-specific detection assays.

We describe a family with beta-thalassemia in which several pitfalls of genetic diagnoses were present. These include coherent family phenotypes with discrepancies in molecular findings because of nonpaternity, and a false beta-globin gene homozygous genotype due to a large deletion in the second locus. These findings underline the difficulties of family genetic studies and the need for tight relationship between professionals involved in laboratory studies and those in-charge of the clinical follow-up and genetic counselling. In this family, we also report a new silent beta-thalassemia mutation, -102 (C>A), in the distal CACCC box of the beta-globin gene promoter.

Inherited factor VII (FVII) deficiency is a rare autosomal disorder characterized by a weak relationship between FVII activity (FVII:C) and operative bleeding risk. We report a retrospective study of 17 patients with a FVII:C below 0.1 IU/ml, in whom surgery was performed without any replacement therapy. Clinical and biological data were analysed to establish predictive criteria for bleeding tendency. We found that systematic preoperative replacement therapy may not be necessary for 'minor' surgical procedures, for patients suffering from inherited FVII deficiency, unless the clinical history includes severe haemorrhagic symptoms such as haemarthrosis, severe haematomas (even of soft tissue) or abundant epistaxis.