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

Abstract

The c.1544+1G4A 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 aIIbb3 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+1G4A at intron 15 descended from a common ancestor 300-400 years ago.

αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia

“…Independent support for the recent origin of GT missense mutations comes from studies of two populations with relatively high rates of GT because of intragroup marriage, namely Israeli and Palestinian Arabs and French Manouche gypsies, in which the founder mutations were estimated to be only ∼300-600 and ∼300-400 y old, respectively (23,24).…”

“…In the past 10 y, high-resolution crystallography, electron microscopy, and computational studies of the αIIbβ3 receptor have provided atomic-level information on the correlation between receptor structure and function (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21). In addition, ethnic groups with relatively high prevalence of GT have been defined that share the same genetic abnormality based on founder mutations, and the dates that some of the mutations entered the population have been estimated (22)(23)(24)(25)(26)(27)(28). An on-line registry of GT abnormalities, including patient phenotypes was developed in 1997 (29) and currently contains 51 αIIb and 43 β3 missense variants linked to Significance Next-generation sequencing is identifying millions of novel gene variants, presenting challenges to researchers and clinicians.…”

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of theITGA2BandITGB3Genes in a Large International Cohort

“…For ITGA2B , we sequenced 416 bp upstream of the promoter and for ITGB3 463 bp upstream. High‐resolution melting (HRM) curve analysis was performed as described [Fiore et al., ].…”

Platelet Receptors

“…Certain mutations predominate in ethnic groups such as in Israel and in the French gypsy population. Recently, the estimated age of the French gypsy mutation founder was 300-400 years (Coller and Shattil 2008;Fiore et al 2011;Kasirer-Friede et al 2007;Nurden 2006;Nurden and Nurden 2008).…”