Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families

The c.1544+1G>A substitution at the 5' splice donor site of intron 15 of the ITGA2B gene, called the French Gypsy mutation, causes Glanzmann thrombasthenia, an inherited hemorrhagic disorder transmitted as an autosomal recessive trait and characterized by an altered synthesis of the platelet alpha IIb beta 3 integrin. So far, this mutation has only been found in affected individuals originating from French Manouche families, strongly suggesting a founder effect. Our goal was to investigate the origin of the French Gypsy mutation. We estimated the age of the mutation by a likelihood-based method that uses the length of the shared haplotypes among a set of patients. For this, we genotyped 23 individuals of Manouche origin; consisting of 9 Glanzmann thrombasthenia patients homozygous for the French Gypsy mutation, 6 heterozygous carriers and 8 homozygous wild-type individuals. They were genotyped for four single-nucleotide polymorphisms using high-resolution melting curve analysis, and for two CA repeats in the BRCA1 and THRA genes at chromosome 17, using fragment analysis gels. We found that a haplotype of five polymorphic loci covering a 4-cM region was strongly associated with the French Gypsy mutation, suggesting a founder effect. The estimated age of this founder mutation was 300-400 years (range 255-552 years). Thus, all carriers of the French Gypsy mutation c.1544+1G>A at intron 15 descended from a common ancestor 300-400 years ago. European Journal of Human Genetics (2011) 19, 981-987; doi: 10.1038/ejhg.2011.61; published online 13 April 2011