The Two Common Mutations Causing Factor XI Deficiency in Jews Stem From Distinct Founders: One of Ancient Middle Eastern Origin and Another of More Recent European Origin

Abstract

Previous studies showed that factor XI (FXI) deficiency commonly observed in Ashkenazi Jews is caused by two similarly frequent mutations, type II (Glu117stop) and type III (Phe283Leu) with allele frequencies of 0.0217 and 0.0254, respectively. In Iraqi Jews, who represent the ancient gene pool of Jews, only the type II mutation was observed with an allele frequency of 0.0167. In this study we sought founder effects for each mutation by examination of four FXI gene polymorphisms enabling haplotype analysis in affected Jewish patients of Ashkenazi, Iraqi, and other origins and in Arab patients. Initial population surveys of 387 Middle Eastern Jews (excluding Iraqi Jews), 560 North African/Sephardic Jews, and 382 Arabs revealed allele frequencies for the type II mutation of 0.0026, 0.0027, and 0.0065, respectively. In contrast, the type III mutation was not detected in any of these populations. All 60 independent chromosomes bearing the type III mutation were solely observed in Ashkenazi Jewish patients and were characterized by a relatively rare haplotype. All 103 independent chromosomes bearing the type II mutation in patients of Ashkenazi, Iraqi, Yemenite, Syrian, and Moroccan Jewish origin and of Arab origin were characterized by another distinct haplotype that was rare among normal Ashkenazi Jewish, Iraqi Jewish, and Arab chromosomes. These findings constitute the first example of a mutation common to Ashkenazi Jews, non-Ashkenazi Jews, and Arabs and are consistent with the origin of type II mutation in a founder before the divergence of the major segments of Jews. Our findings also indicate that the type III mutation arose more recently in an Ashkenazi Jewish individual.

Factor XI deficiency in the French Basque Country

“…Interestingly, type II mutations could be observed in all Jewish communities and probably appeared in ancient times (586 BC BC± ±70 AD AD) before the divergence of the major segments of this population. On the other hand, type III mutations were solely found in Ashkenazi patients and were supposed to arise more recently [26]. In addition, some correlations have been found between the genotype and FXIc levels or bleeding incidence [13].…”

The spectrum of factor XI deficiency in Italy

“…Haplotype analysis demonstrated that these two mutations are of ancient origins and arose from distinct founders [12]. Although the type II mutation is also frequent among Iraqi Jews and Palestinian Arabs [12], Phe283Leu is almost unique in Ashkenazi Jews, but it can be rarely observed in other populations [13,14]. A large study performed in the Italian population, besides confirming the Jewish origin of both type II and III mutations, evidenced a significant frequency of the Glu117Stop allele among Italian FXIdeficient patients [13].…”

“…by pre-surgical screening or during family studies after identification of homozygous subjects) by which these subjects, usually asymptomatic, were identified. Interestingly, the type III Phe283Leu has been identified in compound heterozygosity in two patients only (allele frequency 3.8%), although the frequencies of the type II and type III mutations (allele frequency 0.00064 and 0.00051 respectively) in an unselected population of 3879 Italian individuals were indeed similar [13], as in Askenazi Jewish [11,12]. However, as most FXI-deficient patients remain asymptomatic, a significant number could go unrecognized, thus causing a diagnostic selection bias and a difficulty in a reliable estimate of the complete genetic background.…”

“…Two mutations, designated as type II (Glu117stop) and type III (Phe283Leu), account for 98% of alleles in this population. Haplotype analysis demonstrated that these two mutations are of ancient origins and arose from distinct founders [12]. Although the type II mutation is also frequent among Iraqi Jews and Palestinian Arabs [12], Phe283Leu is almost unique in Ashkenazi Jews, but it can be rarely observed in other populations [13,14].…”

Population‐specific spectrum of the F11 mutations in Koreans: evidence for a founder effect

“…Markers used in Jewish or Italian haplotyping in previous studies are shaded in gray(27,28). b Nucleotide number of the intronic polymorphisms have been assigned starting from the nearest splicing junction.…”