A common ancestor more than 10,000 years old for patients with R854Q-related type 2N von Willebrand's disease in Italy

Abstract

The impaired capacity of von Willebrand factor to carry factor VIII is identified as type 2N von Willebrand's disease. R854Q is the most common type 2N mutation, and almost the only one identified in Italy. This aim of this study was to ascertain whether R854Q mutations in a cohort of Italian patients with type 2N von Willebrand's disease originated from a single event or recurrent events. Thirteen unrelated Italian families were investigated, analyzing the von Willebrand factor gene haplotype associated with the R854Q mutation. A common haplotype emerged in all the families, extending from single nucleotide polymorphisms rs2166902 to rs216293 over 48.2 kb and including five intragenic markers. This haplotype is infrequent in the healthy Italian population (17% versus 100%, P<0.0001) and each genetic marker within the said haplotype is similarly rare. These data strongly suggest a founder effect, with a single R854Q mutation event being the cause of the type 2N von Willebrand's disease in our cohort of patients. Using DMLE+ software and the mathematical model of Bengtsson and Thomson, it was estimated that the R854Q mutation occurred from 10,000 to 40,000 years ago, which is consistent with the short dimension of the haplotype shared by our patients. Together with the fact that the R854Q mutation seems to be limited to Caucasian populations, these findings suggest that a single mutational event took place after human populations moved from Africa towards Europe.

Figure 1.

Geographic distribution of the type 2N VWD families studied in Italy and migration fluxes from Africa to Asia and Europe in the last 100,000 years.

Figure 2.

Schematic map of the nine markers selected (6 single nucleotide polymorphisms and 3 short tandem repeats) flanking the c.2561G>A mutation. The physical position of each marker on chromosome 12 was derived from the UCSC Genome Browser (February 2009 assembly).

Figure 3.

Estimated allele age of the c.2561G>A mutation calculated with the DMLE+ software based on the oscillation in growth rates, considering 0.025 as the growth rate in year 1 AD.