title: A recurrent F8 mutation (c.6046C>T) causing hemophilia A in 8% of northern Italian patients: evidence for a founder effect.
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.
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Garagiola
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Seregni
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Mimosa
authors.initials: M
authors.lastname: Mortarino
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Maria Elisa
authors.initials: ME
authors.lastname: Mancuso
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: Fasulo
authors.affiliation: Pediatric Onco-Hematology and BMT Unit Children Hospital Spedali Civili Brescia Italy.
authors.forename: Lucia Dora
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Angelo Bianchi Bonomi Haemophilia and Thrombosis Center Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico Università degli Studi di Milano and Luigi Villa Foundation Milan Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Peyvandi
keywords: F8 gene; founder effect; haplotype analysis; hemophilia A; recurrent mutation