Type I mutation in the F11 gene is a third ancestral mutation which causes factor XI deficiency in Ashkenazi Jews

Summary. Background: Factor XI (FXI) deficiency is oneof the most frequent inherited disorders in AshkenaziJews (AJ). Two predominant founder mutations termedtype II (p.Glu117Stop) and type III (p.Phe283Leu)account for most cases. Objectives: To present clinicalaspects of a third FXI mutation, type I (c.1716 + 1G>A),which is also prevalent in AJ and to discern a possiblefounder effect. Methods: Bleeding manifestations, FXIlevels and origin of members of 13 unrelated families har-boring the type I mutation were determined. In addition,eight intragenic and five extragenic polymorphisms wereanalyzed in patients with a type I mutation, in 16 unre-lated type II homozygotes, in 23 unrelated type III homo-zygotes and in Ashkenazi Jewish controls. Analysis ofthese polymorphisms enabled haplotype analysis and esti-mation of the age of the type I mutation. Results: Fourof 16 type I heterozygotes (25%) and 6 of 12 (50%) com-pound heterozygotes for type I mutation (I/II and I/III),or a type I homozygote had bleeding manifestations.Haplotype analysis disclosed that like type II and type IIImutations, the type I is also an ancestral mutation. Anage estimate revealed that the type I mutation occurredapproximately 600 years ago. The geographic distributionof affected families suggested that there was a distinct ori-gin of the type I mutation in Eastern Europe. Conclu-sions: The rather rare type I mutation in the FXI gene isa third founder mutation in AJ.Keywords: Ashkenazi Jews, factor XI, factor XI defi-ciency, factor XI mutations, polymorphisms.IntroductionFactor XI (FXI) deficiency, a mild to moderate injury-related inherited bleeding disorder [1], is one of the mostfrequent genetic disorders in Ashkenazi Jews (AJ) [2,3].After the cloning and sequencing of the F11 gene [4],three types of point mutations were identified in six FXI-deficient patients of AJ origin: a donor splice site muta-tion (c.1716 + 1G>A) in the last intron-N of the F11 genewhich was termed a type I mutation; a nonsense mutationp.Glu117Stop which was termed a type II mutation and amissense mutation p.Phe283Leu termed a type III muta-tion [5]. The type II and type III mutations are the pre-dominant mutations causing FXI deficiency among AJpatients [6]. Whereas the type III mutation was exclu-sively identified in AJ, the type II mutation was fre-quently observed also in Iraqi Jews who represent theoriginal gene pool of the Jews [7]. Haplotype analysisdemonstrated two distinct founders of the type II andtype III mutations [8]. The different ethnic distributionand the estimated coalescence times of 120–189 and31–100 generations for the type II and type III mutations,respectively, suggested an ancient Middle Eastern originfor the type II mutation and a more recent European ori-gin for the type III mutation [8,9].The aim of the present study was to investigate theclinical and genetic aspects of the less common type Imutation in AJ, to delineate a potential founder effect, toestimate the age of the mutation and to assess the geo-graphic origin of affected families.MethodsPatients and control subjectsFourteen AJ FXI-deficient probands who carry the type Imutation were identified among FXI-deficient families fol-lowed at our clinic. Also studied were 32 available familymembers of type I probands, 16 AJ type II homozygotes,23 AJ type III homozygotes and 438 AJ controls. The