Abstract

Hemophilia A is a heterogeneous hemorrhagic disorder caused by a large number of mutations. Recurrent mutations are rare, except intron 22 and intron 1 inversions. The substitution of a cytosine to a thymine at nucleotide 6046 in F8 gene was identified in a group of Italian patients affected by hemophilia A from a specific region of Northern Italy with a prevalence of 7.6%. This F8 variant was the second most frequent mutation in our cohort, after the intron 22 inversion. The identification of the same mutation in a restricted population gets to suppose the existence of a founder effect. Intragenic and extragenic polymorphic markers were tested to assess this assumption. A peculiar haplotype in linkage disequilibrium with this recurrent mutation (c.6046C>T) was identified in 71% of patients, supporting a founder effect. This distinctive haplotype was not identified in a control group (Fisher's exact test, P < 0.0001), coming from the same geographic region. These data strongly suggested the presence of a founder effect, supporting the existence of a single mutation event. Using DMLE+2.3 software and the mathematical approach described by Bengtsson and Thomson, the inferred age of this mutation is supposed to be about 2325 years (95% CI: 904–5081) ago.

Highlights

  • Up to date, more than 100 X-linked inherited human disorders or traits have been identified, most of which are classified as recessive (McKusick 1998)

  • Patients carrying the c.6046C>T substitution have shown variable factor VIII (FVIII):C ranging from

  • We identified a mutation of F8 (c.6046C>T) that is the second most frequent in our patients affected by hemophilia A, after the intron 22 inversion with a prevalence of 7.6%

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Summary

Introduction

More than 100 X-linked inherited human disorders or traits have been identified, most of which are classified as recessive (McKusick 1998). Among the human X-linked recessive diseases, hemophilia A (HA; MIM #306700) represents the most common hereditary bleeding disorder, determined by decreased factor VIII (FVIII) levels in plasma with a proportional reduction in FVIII clotting activity (FVIII:C). On the basis of residual FVIII:C, hemophilia is categorized in three main forms: severe (FVIII: C < 1 IU/dL), moderate (FVIII:C 1–5 IU/dL), and mild (FVIII:C 6–39 IU/dL) (Mannucci and Tuddenham 2001). Recurrent hemarthroses may cause in these patients crippling arthropathy on the long-term if not properly treated (Mannucci and Tuddenham 2001)

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