Severe factor XI deficiency in the Abruzzo region of Italy is associated to different FXI gene mutations

Factor XI (FXI) deficiency is an autosomal inherited coagulation disorder characterized by bleeding symptoms mainly associated with injury or surgery. Although most of the FXI gene mutations in Ashkenazi Jews are represented by the Glu117stop or Phe283Leu mutations, considerable genetic heterogeneity has been reported in other populations. We report here the genotypic characterization of four families with severe inherited FXI deficiency from the Czech Republic. Seven different gene mutations (three novel) were identified, thus, excluding the existence of a major founder effect in this population. Interestingly, both Glu117-stop and Phe283Leu were detected once, further demonstrating the occurrence of these mutations also outside the Jewish populations. In conclusion, we confirm that FXI deficiency in non-Jewish populations is because of different gene mutations; however, the presence of the Glu117stop and Phe283Leu mutations suggests that genetic testing in FXI-deficient patients can start with these two point mutations. Am. J. Hematol. 83:916-919, 2008. V

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“…Our results confirm that the molecular basis of this disorder is largely heterogeneous outside the Jewish population [11][12][13]26].…”

Section: Discussionsupporting

confidence: 78%

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

et al. 2008

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“…To sum up, evidence provided by different studies in patients from Italy suggests that the genetic background is largely heterogeneous among Italian patients with FXI deficiency and that the type II mutation is the only founder mutation. Apart from a peculiar cluster in north-eastern Italy carrying Ile436Lys mutation [29], among the causative mutations identified in 33 (66 alleles) apparently unrelated patients with severe FXI deficiency (FXI:C < 10 U dL À1 ), including the present ones, four homozygous and four compound heterozygous Glu117Stop patients were identified (allele frequency 18%) [13,22,23,[29][30][31][32][33]. Similar frequencies have been observed among the >100 heterozygous subjects so far described, including those here reported, but this estimation is of course influenced by the criteria (e.g.…”

Section: Genetic Heterogeneity Of Fxi Deficiency In Italymentioning

confidence: 83%

“…30 disease-associated alleles were found, 10 of which hitherto not known. In particular, of the eight severe patients, four were truly homozygous and four compound heterozygous, with some mutations previously reported [22,23]. Thirteen additional heterozygous relatives were identified by genetic analysis in these families, none with any bleeding tendency.…”

Section: In Addition Low Vwf (48 U DL à1mentioning

confidence: 85%

The spectrum of factor XI deficiency in Italy

et al. 2013

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Factor XI (FXI) deficiency is a rare inherited bleeding disorder invariably caused by mutations in the FXI gene. The disorder is rather frequent in Ashkenazi Jews, in whom around 98% of the abnormal alleles is represented by Glu117X and Phe283Leu mutations. A wide heterogeneity of causative mutations has been previously reported in a few FXI deficient patients from Italy. In this article, we enlarge the knowledge on the genetic background of FXI deficiency in Italy. Over 4 years, 22 index cases, eight with severe deficiency and 14 with partial deficiency, have been evaluated. A total of 21 different mutations in 30 disease-associated alleles were identified, 10 of which were novel. Among them, a novel Asp556Gly dysfunctional mutation was also identified. Glu117X was also detected, as previously reported from other patients in Italy, while again Phe283Leu was not identified. A total of 34 heterozygous relatives were also identified. Bleeding tendency was present in very few cases, being inconsistently related to the severity of FXI deficiency in plasma. In conclusion, at variance with other populations, no single major founder effect is present in Italian patients with FXI deficiency.

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“…Interestingly, we observed the type III mutation in 2 patients. To date, only 2 Italian patients with the p.Phe301Leu have been described 8 , 23 and both individuals were compound heterozygotes showing a bleeding tendency. In the present study, p.Phe301Leu was detected in combination with nonsense or splice site mutations.…”

Section: Discussionmentioning

confidence: 99%

Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype–phenotype relationship

et al. 2017

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Congenital Factor XI (FXI) deficiency shows a high variability in clinical phenotype. To date, many allele variants have been shown to cause this bleeding disorder. However, the genotype–phenotype relationship is difficult to establish. This report provides insights into this bleeding disorder. Sixteen unrelated Italian index cases with congenital FXI deficiency and their relatives were investigated. After the identification of the deficiency, we obtained DNA from each subject and analyzed the FXI gene using direct sequencing. We identified 5 and 11 individuals with severe and moderate deficiency of FXI activity, respectively. Most patients (8/16) carried mutations in the Apple 2 domain and 4 patients showed c.403G>T (p.Glu135*; type II mutation). Four novel compound heterozygosities were identified. Bleeding symptoms were present in two severely deficient subjects carrying the combinations c.901T>C (p.Phe301Leu)/c.1556G>A (p.Trp519*) and c.943G>A (p.Glu315)/c.1556G>A (p.Trp519*), respectively. Bleeding episodes were also observed in the presence of a moderate deficiency in two individuals heterozygous for c.449C>T (p.Thr150Met) and c.1253G>T (p.Gly418Val), respectively. One novel mutation, c.1682C>A (p.Ala561Asp), was identified as potentially deleterious in an asymptomatic individual. We confirm an unclear prediction of phenotype from mutational data. The FXI levels should be coupled with FXI analysis for a more comprehensive prediction of the bleeding phenotype in FXI deficiency.

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Severe factor XI deficiency in the Abruzzo region of Italy is associated to different FXI gene mutations

Cited by 6 publications

References 10 publications

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

Factor XI gene mutations in factor XI deficient patients of the Czech Republic

The spectrum of factor XI deficiency in Italy

Factor XI gene variants in factor XI-deficient patients of Southern Italy: identification of a novel mutation and genotype–phenotype relationship

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