A recurrent F8 mutation (c.6046C>T) causing hemophilia A in 8% of northern Italian patients: evidence for a founder effect. Issue 2 (14th December 2015)

• Record Type: Journal Article
• Authors: Garagiola, Isabella; Seregni, Sabrina; Mortarino, Mimosa; Mancuso, Maria Elisa; Fasulo, Maria Rosaria; Notarangelo, Lucia Dora; Peyvandi, Flora
• Is Part Of: Molecular genetics & genomic medicine. Volume 4:Issue 2(2016)
• Page Start: 152
• Page End: 159
• Publication Date: 2015-12-14
• Subjects: F8 gene -- founder effect -- hemophilia A -- haplotype analysis -- recurrent mutation; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.189
• Languages: English
• ISSNs: 2324-9269

Abstract

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. Abstract : Among 300 hemophilia A Italian patients screened for F8 gene mutations, a recurrent mutation (c.6046C>T) was identified in a group of patients 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. A haplotype analysis was performed to investigate the existence of a founder effect associated to the recurrent mutation. The data obtained from haplotype analysis strongly suggested the presence of a founder effect, supporting the existence of a single mutation event. Using DMLE+ software and a mathematical approach, we also estimated the age of this mutation.