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Keywords:

  • Ashkenazi Jews;
  • factor XI;
  • factor XI deficiency;
  • factor XI mutations;
  • polymorphisms

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Background

Factor XI (FXI) deficiency is one of the most frequent inherited disorders in Ashkenazi Jews (AJ). Two predominant founder mutations termed type II (p.Glu117Stop) and type III (p.Phe283Leu) account for most cases.

Objectives

To present clinical aspects of a third FXI mutation, type I (c.1716 + 1G>A), which is also prevalent in AJ and to discern a possible founder effect.

Methods

Bleeding manifestations, FXI levels and origin of members of 13 unrelated families harboring the type I mutation were determined. In addition, eight intragenic and five extragenic polymorphisms were analyzed in patients with a type I mutation, in 16 unrelated type II homozygotes, in 23 unrelated type III homozygotes and in Ashkenazi Jewish controls. Analysis of these polymorphisms enabled haplotype analysis and estimation of the age of the type I mutation.

Results

Four of 16 type I heterozygotes (25%) and 6 of 12 (50%) compound 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 III mutations, the type I is also an ancestral mutation. An age estimate revealed that the type I mutation occurred approximately 600 years ago. The geographic distribution of affected families suggested that there was a distinct origin of the type I mutation in Eastern Europe.

Conclusions

The rather rare type I mutation in the FXI gene is a third founder mutation in AJ.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Factor XI (FXI) deficiency, a mild to moderate injury-related inherited bleeding disorder [1], is one of the most frequent 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 mutation (c.1716 + 1G>A) in the last intron-N of the F11 gene which was termed a type I mutation; a nonsense mutation p.Glu117Stop which was termed a type II mutation and a missense mutation p.Phe283Leu termed a type III mutation [5]. The type II and type III mutations are the predominant mutations causing FXI deficiency among AJ patients [6]. Whereas the type III mutation was exclusively identified in AJ, the type II mutation was frequently observed also in Iraqi Jews who represent the original gene pool of the Jews [7]. Haplotype analysis demonstrated two distinct founders of the type II and type III mutations [8]. The different ethnic distribution and the estimated coalescence times of 120–189 and 31–100 generations for the type II and type III mutations, respectively, suggested an ancient Middle Eastern origin for the type II mutation and a more recent European origin for the type III mutation [8, 9].

The aim of the present study was to investigate the clinical and genetic aspects of the less common type I mutation in AJ, to delineate a potential founder effect, to estimate the age of the mutation and to assess the geographic origin of affected families.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Patients and control subjects

Fourteen AJ FXI-deficient probands who carry the type I mutation were identified among FXI-deficient families followed at our clinic. Also studied were 32 available family members of type I probands, 16 AJ type II homozygotes, 23 AJ type III homozygotes and 438 AJ controls. The type I probands and family members were questioned about the exact origin of their parents and grandparents. The control subjects consisted of consecutively admitted AJ patients to the Departments of Internal Medicine and General Surgery at the Tel Aviv Sourasky Medical Center. The parental origins of the controls were: Poland 405, Russia 143, Romania 136, Ukraine 43, Lithuania 27, Germany 27, Czechoslovakia 26, Hungary 19, Belarus 16, Austria 13, Israel 7, Moldavia 6, Latvia 5, Finland 2 and Greece 1. The study was approved by the Institutional Review Board of the Sheba Medical Center.

DNA analysis

Genomic DNA was extracted from peripheral blood using a standard procedure. The type I mutation was detected by fluorescent hybridization probe melting curves in RT-PCR on a Light Cycler instrument (Roche Diagnostics GmbH, Mannheim, Germany) as shown in the supplementary Table S1 and Fig. S1, or by restriction analysis [10]. Type II and type III mutations were identified as previously reported [10].

Eight polymorphic markers within the F11 gene, including four previously examined by us were analyzed [8]. Five polymorphic markers flanking the F11 gene were also analyzed by PCR-based assays as detailed in Table S1.

Derivation of haplotypes

Haplotypes of the F11 intragenic and extragenic polymorphisms in the normal and mutated chromosomes were determined by segregation analysis in the studied families. In addition, haplotypes of the intragenic markers associated with the type II and type III mutations were derived by genotyping unrelated homozygous type II and type III patients, respectively.

Age estimates of the FXI type III and type I mutations

Estimation of the age of the FXI type III and type I mutations was carried out by the DMLE + 2.0 software program (www.dmle.org) which was designed for high-resolution mapping of disease-causing mutations and for estimating the age of mutations [11, 12]. The program uses the Markov Chain Monte Carlo algorithm to allow Bayesian estimation of the mutation age based on the observed linkage disequilibrium between the mutation and flanking polymorphic markers in DNA samples from affected and unaffected individuals. For estimation of the age of the type I and type III mutations by the DMLE + 2.0 program, we used the following data: (i) genotypes of polymorphic markers in 45 control chromosomes, 46 chromosomes harboring the F11 type III mutation and 14 chromosomes carrying the F11 type I mutation; (ii) chromosomal map distances between the polymorphic markers and disease-causing mutations that were taken from the reference sequence assembly map disclosed on June 6, 2012 http://www.ncbi.nlm/nih.gov/SNP; (iii) the growth rate (r) of the AJ population. This rate was estimated from the equation: T1 = T0e(gr), where T1 is the estimated size of the AJ population at the present time (approximately 11 000 000), T0 is the estimated size of the eastern European ancestral population, i.e. 7000 in 1170 AD [13] and 10 000–20 000 in 1500 AD [14], and g is the number of generations between T1 and T0 assuming 20 years per generation. The T0 records from 1170 AD and from the end of the 15 century yielded r values of 0.175 and 0.26, respectively. An average r value, 0.22, was used for calculations of the age of mutations; (iv) estimated allele frequencies of the F11 type III and type I mutations in the general AJ population. The estimated allele frequency of the type III mutation, 0.025, was taken from a previously published survey of 531 Ashkenazi Jewish controls [7]. As no type I mutation was detected in 438 AJ controls, we assessed the allele frequency by comparing the frequency of the type I alleles to the combined frequency of type II and type III alleles among unrelated severe FXI-deficient AJ patients followed up at our clinic. In our severe FXI-deficient cohort of 414 patients, we identified 10 FXI type I alleles, 434 AJ type II alleles and 363 type III alleles (Table 1). Thus, the proportion of type I among AJ type II + III alleles was 0.01255. We previously estimated the allele frequency of the type III and type II mutations in the general AJ population to be 0.0467 (0.025 type III + 0.0217 type II) [7]. This allowed us to estimate that the allele frequency of the FXI type I mutation in the general AJ population is 0.01255 × 0.0467 = 0.000586.

Table 1. Relative frequency of F11 mutant alleles in 414 unrelated Jewish patients with severe FXI deficiency
Mutant allele N %
  1. a

    Four hundred and thirty-four mutant alleles are present in Ashkenazi Jewish patients.

  2. b

    All mutant alleles are of Ashkenazi Jewish patients.

Type II-p.Glu117stop446*53.9
Type III-p.Phe283Leu363b43.8
Type I- c.1716 + 1G>A10b1.21
Type IV-c.1714_1716 + 11del20.24
p.Gly555Glu20.24
p.Tyr427Cys10.12
p.Glu323Lys10.12
c.73del1410.12
Unknown20.24
 828100

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

Relative frequency of the type I mutation in FXI-deficient patients

Among 414 unrelated Israeli Jewish patients with FXI levels of less than 15U dL−1 followed at the Sheba and Sourasky Medical Centers during the last four decades, the allele frequency of the type I mutation was 1.21% compared with a frequency of 53.9% and 43.8% for the type II and type III mutations, respectively (Table 1). Additional patients with the type I mutation were detected in heterozygous carriers who presented with partial FXI deficiency during routine coagulation testing in families 1, 4 and 8 (Table 2). In family 3 there were two probands who were independently ascertained; one was a type I homozygote and the other was a type I/II compound heterozygote (Fig. 1). Altogether, the type I mutation was identified in Israel in 13 unrelated AJ families (Fig. S2). The type I mutation was not detected in 438 AJ control subjects.

Table 2. FXI activity and bleeding manifestations in affected members of 13 families with type I FXI deficiency
FamilySubjectGenotypeFXI act. (U dL−1)Bleeding history
1Index caseI/-38Menorrhagia, epistaxis
MotherI/-48Oozing after extirpation of skin lesion, menorrhagia
2Index caseI/-32 
MotherI/-46 
HusbandIII/-- 
SonI/III4 
3Index case-1I/I< 1 
BrotherI/-40 
Index case-2I/II< 1Bleeding after trauma to penis
MotherI/-41 
FatherII/-31 
4Index caseI/-34Injury related, epistaxis
FatherI/-43 
SisterI/-43 
5Index caseI/III2 
MotherI/-62 
FatherIII/-77 
6Index caseI/-45Menorrhagia, after injury and tooth extraction
MotherI/II1Postpartum bleeding
7Index caseI/II< 1Bleeding after prostatectomy, tetanus vaccination
SonI/-38 
DaughterI/II< 1Menorrhagia, postpatum bleeding, easy bruising
Grandson 1I/-49 
Grandson 2II/-64 
Grandson 3II/-59 
8Index caseI/-29 
9Index caseI/III2 
DaughterI/-35 
10Index caseI/III1 
SonIII/-- 
GrandsonIII/-- 
11Index caseI/III2Bleeding following circumcision
MotherI/-52 
FatherIII/-60 
12Index caseI/III2 
SonII/III3 
13Index caseI/II< 1Menorrhagia, ecchymoses
image

Figure 1. Pedigree of family 3 showing the type I founder haplotype (shaded). The two probands are marked by arrows, and the year of birth and parental origins are depicted at the top of the male and female symbols. Full black, vertical grid and horizontal grid within symbols represent in this Fig. and Fig. S2 type I, type II and type III mutated alleles, respectively. The haplotypes are shown below the symbols and include from top to bottom alleles of polymorphic markers at the following loci: D4S171 (CAn), TLR3, DKFZ/FAM149A, CYP4V2, F11 [intron A (c.1 -230 C>T, c.1 -150–151 delAT, c.1 -139 A>C), intron B (c.55 + 3459 CAn, c.55 + 3442 G>A), intron E (c.486–431 G>A, c.486–361 C>T), intron M (c.1576 + 1083 ATn), type of mutation] and MTNR1A. Horizontal lines separate the intragenic markers from the centromeric markers (upper lines) and telomeric markers (lower lines). Alleles are depicted by number of repeats or by the actual base as appropriate. In intron A, the delAT allele is designated by ∆ and the wild-type allele is designated by W. The remaining 12 pedigrees and haplotypes are shown in Fig. S2.

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FXI activity and clinical manifestations in patients harboring the type I mutation

FXI activity and bleeding manifestations in members of the 13 studied families who harbored at least one type I allele are summarized in Table 2. The mean (± SD) FXI level in 16 type I heterozygotes was 42.2 (± 8.2) U dL−1. Four of these heterozygotes exhibited a bleeding tendency (menorrhagia in 3 and injury-related bleeding in 4). A mean FXI activity of less than 1U dL−1 was found in five compound heterozygotes for the type I and type II mutation and in the homozygote for the type I mutation. The FXI antigen level in the type I homozygote was 0.35 U dL−1 (0.3%). Six patients were compound heterozygotes for the type I and type III mutation. Their mean (± SD) FXI activity was 2.2 (± 1) U dL−1. Altogether, among the 12 patients with severe FXI deficiency (type I/II compound heterozygotes, type I/III compound heterozygotes and type I homozygote), three had injury-related bleeding, two had menorrhagia and two had postpartum bleeding. Six patients had no bleeding manifestations.

Demonstration of a founder effect for the type I mutation

A unique haplotype encompassing the intragenic polymorphic markers (CWA11GGC9) that segregated with the type I mutation was discerned in the affected families. Enhanced informativity was obtained by definition of extended type II and type III founder haplotypes [7] (CWA11GGC8 and TΔA10GGC8, respectively) in unrelated type II and type III homozygotes and by segregation analysis in informative families for the type II mutation, families 3 and 7, and for the type III mutation, families 2, 5, 10, 11 (Fig. 1, Fig. S2, Fig. 2). Thus, the type I haplotype was defined in 12 of 13 families. Family 8 was not informative but the results were consistent with the same haplotype. In contrast to the type I, II and III haplotypes, analysis of 25 independent normal chromosomes yielded 11 different intragenic haplotypes as follows: TWC9AAT8, 7/25, TWA11GGC8, 4/25, CWA11GGC8, 3/25, TWA9AAT8, 2/25, CWA11GGC9, 2/25, TΔA10GGC8, 2/25, TWA9AAC8, 1/25, CWC11GGT9, 1/25, TWA9AAT9, 1/25, TWA11GGC9, 1/25 and TWC11GGC9, 1/25 (Fig. 2). The frequency of the type I-specific haplotype among normal chromosomes was 8% (2/25).

image

Figure 2. Frequency distribution of intragenic FXI haplotypes in type I, type II and type III mutants and control chromosomes.

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The haplotype associated with the type I mutation extended beyond the FXI intragenic region (Fig. 1 and Fig. S2). The same allele (G) of the MTNR1 gene SNP located about 270 kb telomeric to the F11 gene was completely conserved in contrast to a frequency of 57.8% (26/45) in the normal chromosomes. The C allele of the extragenic marker of the CYP4V2 gene located approximately 80 kb centromeric to the FXI gene was also conserved in 11/13 families. In the remaining two families, the results were not conclusive but consistent with the same association. The frequency of the C allele among the control chromosomes was 51.1% (23/45). Moreover, in more than half of the studied families (families 3, 5, 7, 8, 9, 10, 11), the data were consistent with a type I specific haplotype (20TACCWA11GGC9G) spanning 1.43 Mb. This haplotype was not found in 25 informative normal chromosomes. Taken together, the results clearly define a founder effect for the type I mutation.

Geographic distribution of the type I mutation

Information was obtained on the origins of 11 out of the 13 affected families (Fig. 1, Fig. S2). Except for family 3, tracing of the mutation to the maternal or paternal lineages was not possible. Nevertheless, in most families, the origin of the parental lineages was from close geographic regions. In six families (families 2, 5, 6, 10, 12, 13) at least one ancestor originated from Romania, mostly from the northern regions of Transylvania (e.g. Sziget and Petrosani) and Moldova (e.g. Iasi, Bacau and Vaslui). In four other families (families 1, 3, 4, 11), at least one ancestor originated from territories flanking northern Romania that are currently part of Ukraine (e.g. Munkacs, Lemberg, Buczacz and Odessa). Three families (families 1, 3 and 10) were of mixed Ukrainian-Romanian ancestry. Additional ancestors originated in neighboring Eastern European countries (Belarus, Poland and the Czech Republic), and in some instances from towns near the Ukraine border (Chelm and Pinsk) (Fig. 1, Fig. S2). Of special interest was the information obtained from families 3 and 10. In family 3, information was provided on four previous generations that originated in Transylvania and Maramures (a northern region of Transylvania). However, one generation back, their common ancestors that were born at the end of the 19th century originated from Lemberg which, at that time, was the capital city of the Kingdom of Galicia (currently Lviv) located in western Ukraine. The history of family 10 disclosed that the type I mutation was at least 200 years old as the ancestors of the mother and father of the proband immigrated to Israel from Romania and from Ukraine in 1780 and in the early 1800s, respectively.

Estimation of the age of the FXI type III and type I mutations

Figure 3 shows the posterior probability densities of the mutational ages for FXI type III and type I mutations. The FXI type III density peaked at 46 generations. Assuming 20 years for one generation, the estimated age of the type III mutation was 920 years (95% credible set of 800–1160 years). The FXI type I density peaked at 28 generations, giving an estimated age of 560 years (95% credible set of 420–860 years).

image

Figure 3. Age estimates of the FXI type III and type I mutations by the DMLE + 2.0 program. The posterior probability densities of the mutation age (in generations) of the FXI type III and type I mutations are shown. The vertical broken line represents the number of generations that had the highest probability (Peak). The 95% credible set (CS) of values for each posterior density is indicated.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

The type I mutation (c.1716 + 1G>A) is a severe, splice site mutation. A homozygote for type I mutation and type I/II compound heterozygotes exhibit FXI activity of less than 1U dL−1 whereas heterozygotes for type I mutations display FXI levels of 42.2 ± 8.2 U dL−1 (Table 2). Bleeding tendency varied in both severe and partially deficient patients yet was twice as frequent in homozygous or compound heterozygous patients (6/12 bleeders) as compared with heterozygous carriers (4/16 bleeders). In most cases, bleeding occurred at sites with high fibrinolytic activity as previously reported for patients with type II and type III mutations [15, 16]. Another possible cause for bleeding variability is the general hemostatic status of the affected individuals. Recent investigations in patients with heterozygous FXI deficiency showed that the risk of bleeding was associated with lower plasma levels of von Willebrand factor and thrombomodulin [17] and that the thrombin generation test in platelet-rich plasma may be a useful tool to predict bleeding risk [18]. These parameters were not investigated in the present study but warrant further work in the future.

The type I mutation is rare compared with the type II and type III mutations causing FXI deficiency in Jews [7]. Since the first description of the type I mutation in the United States in an AJ more than 20 years ago [5], we have detected 13 unrelated families among AJ living in Israel who harbor the type I mutation (Table 2). Haplotype analysis demonstrated a founder effect for this mutation as was previously shown and now reconfirmed for the type II and type III mutations [8] (Fig. 2). Based on analysis of extragenic polymorphic markers and using the DMLE + 2.0 linkage disequilibrium mapping program, it was estimated that the type I mutation occurred about 600 years ago whereas the type III mutation occurred about 900 years ago. The density peak at 46 (40–58) generations for the FXI type III mutation obtained by the current approach is in good agreement with the previously estimated coalescence times of 31–100 generations obtained by a Markov model representation approach using a single flanking microsatellite marker (D4S171) [9]. These age estimates for the type III mutation coincide with the consolidation of AJ in Europe during the 10–11th century AD and are consistent with its confinement and high prevalence in AJ in Israel [7] and with reports on its rare presence in populations of European descent [19-23]. The type I mutation occurred more recently and is therefore less dispersed. The best definition of the geographic area that links the places of origin of the families carrying the type I mutation is the area in Eastern Europe surrounding the Carpathian mountains. Based on the family histories including that of family 3, it can be speculated that the mutation occurred somewhere in Galicia (today Ukraine) and spread to neighboring countries, especially northern Romania.

The type I mutation in an AJ patient was described only once outside Israel [5] and was not detected in 438 Israeli AJ controls. The very low current prevalence of the type I mutation can be related to the fact that more than two-thirds of the Jewish population from the regions discussed did not survive the holocaust. Also, it should be noted that the AJ control samples examined in the present study included only 20% (179/876) chromosomes of Ukrainian or Romanian-Ukrainian origin. Future surveys of the type I mutation in the Jewish and non-Jewish Ukrainian/Romanian populations may allow better estimation of the prevalence of the type I mutation. Similar regional ancestral mutations in the F11 gene were reported in France [24-26], the UK [27], northern Italy [28] and Korea [29].

In summary, the present study contributes biochemical and clinical characterization of the type I mutation and provides a new piece of information to the historic background of the Jewish genetic disorders. The ancestral type II, type III and type I mutations causing FXI deficiency reflect major landmarks along the Jewish history: the formation of the Jewish nation in the Middle East in the early antiquity, the consolidation of the AJ community at the turn of the late antiquity to the middle ages in Central Europe and the foundation of Eastern European AJ communities between the 12th to 19th centuries, respectively [30].

Addendum

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

H. Peretz: performed the laboratory work and analyzed the data with the technical assistance by S. Usher, M. Zucker, and A. Zivelin; H. Peretz: wrote the paper together with U. Seligsohn; R. Mor-Cohen: performed the age estimates of the mutations; O. Salomon, U. Seligsohn and H. Peretz: designed the study; O. Salomon and U. Seligsohn: collected the blood samples and interviewed members of the affected families.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information

The technical assistance of Eti Zwang, Rusa Eichel and Ilia Tamarin is highly appreciated. We are also indebted to Professor Moshe Friedman and Professor Joel Zlotogora for fruitful consultations.

References

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  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Addendum
  8. Acknowledgements
  9. Disclosure of Conflict of Interests
  10. References
  11. Supporting Information
FilenameFormatSizeDescription
jth12137-sup-0001-FigS1.TIFimage/tif2499KFigure S1. RT-PCR melting curves showing detection of the type 1 mutation.
jth12137-sup-0002-FigS2a.tifimage/tif493KFigure S2. Pedigrees of 12 families with members harboring the type I mutation. For details see legend to Fig. 1.
jth12137-sup-0003-FigS2b.tifimage/tif767KFigure S2. Continued.
jth12137-sup-0004-TableS1.docWord document40KTable S1. Assays used for analysis of the type I mutation and polymorphisms within the F11 gene and flanking loci.

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