Characterization of seven novel mutations causing factor XI deficiency

Zucker, Michal; Zivelin, Ariella; Landau, Meytal; Salomon, Ophira; Kenet, Gili; Bauduer, Frédéric; Samama, M; Conard, J.; Denninger, Marie‐Hélène; Hani, A.; Berruyer, Micheline; Feinstein, Donald I.; Seligsohn, Uri

doi:10.3324/haematol.11526

Cited by 26 publications

(29 citation statements)

References 24 publications

(27 reference statements)

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“…CM053240 (c.1247G>A), responsible for the missense change p.Cys416Tyr, was identified in 7 unrelated index cases (Table ). This mutation was originally described in a Portuguese patient with FXI deficiency and in 8 further unrelated patients . As previously described, this mutation associated with a CRM‐deficiency in carriers from our cohort (Figure ).…”

Section: Resultssupporting

confidence: 76%

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High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study

et al. 2017

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Section: Resultssupporting

confidence: 76%

“…Finally, we identified the first case of FXI deficiency caused by a large insertion. So far only three gross gene defects, all involving deletions of F11 , have been identified among patients with FXI deficiency . We describe the first family with a gross insertion of a duplicated region of F11 .…”

Section: Discussionmentioning

confidence: 95%

High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study

et al. 2017

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“…A total of 10 different mutations, four being novel, were identified in 10 families, confirming the genetic heterogeneity of the disease. Of these 10 mutations, three nonsense, two splice site mutations and one missense mutation have previously been described [15][16][17][18][19][20][21][22][23]. The p. Glu135 Ã (type II) mutation was identified in five individuals from two unrelated families with no known Jewish ancestry.…”

Section: Discussionmentioning

confidence: 98%

Molecular basis and bleeding manifestations of factor XI deficiency in 11 Turkish families

Keskin¹,

Gürsel

Kaya

et al. 2015

Blood Coagulation &Amp; Fibrinolysis

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Factor XI (FXI) deficiency is an autosomal bleeding disorder characterized by variable bleeding tendency. In the present study, the gene encoding FXI (F11) was analyzed by direct sequencing in 33 individuals belonging to 11 unrelated Turkish families, and the bleeding tendency was quantitatively assessed by means of a bleeding questionnaire in 27 individuals with low FXI clotting activity and/or mutated F11 gene. We identified 10 distinct mutations (five missense, three nonsense and two splice site), four of which were novel. No mutation was found in one family. Of the four novel mutations, homozygosity for a c.89T>C (p.Phe30Ser) mutation and compound heterozygosity for a c.646G>A (p.Asp216Asn) mutation with the known c.403G>T (p.Glu135) type II Jewish mutation were associated with severe deficiency, whilst heterozygosity for the novel c.1655A>C (p.His552Arg) and c.1627G>A (p.Glu543Lys) mutations was associated with partial deficiency. p.Glu135 was found in 19% (5/27) of the mutated alleles. Bleeding score was positive in 57% (4/7) of individuals with severe and 39% (7/18) of those with partial deficiency. It was significantly correlated with clinical severity of bleeding (r = 0.43, P = 0.02), but not with FXI clotting activity (P > 0.05). There was no optimal cut-off level of the bleeding score that could predict FXI deficiency. We conclude that the spectrum of mutations found in this study reflects the genetic heterogeneity of FXI deficiency in the Turkish population. Quantitative assessment of the bleeding symptoms by a bleeding questionnaire seems to be useful for evaluating the severity of bleeding episodes, but it can not be recommended as a screening tool for FXI deficiency.

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“…There is also a compound heterozygous Gln 433 Glu + G insertion (12). Finally, there is another compound heterozygote Tyr 427 Cys associated with Glu 117 stop (37). This last case is similar to the compound heterozygote presented in this paper.…”

Section: Discussionmentioning

confidence: 99%

A cluster of factor XI‐deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy*

Girolami

Scarparo

Bonamigo

et al. 2011

European J of Haematology

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A new mutation (Ile 436 Lys) was found in a cluster of patients in northeastern Italy. The mutation was present in five patients at the homozygote level and in one patient as a compound heterozygote with an already known mutation namely Glu 117 stop. All these patients showed a mild bleeding tendency mainly associated with deliveries or surgery. The first two patients were two sisters, and their parents were consanguineous. The third patient was the only homozygote in the family, and parents apparently were not consanguineous. The fourth and fifth patients were a brother and a sister, and in this case too, parents were not consanguineous. The sixth patient, a compound heterozygote, negated also the existence of consanguinity between his parents. There were also seven heterozygotes among the family members of the patients homozygous for this new mutation (Ile 436 Lys). Finally, there were two heterozygotes for the Glu 117 stop mutation in the family of the sixth patient. The heterozygotes, regardless of the mutation, were asymptomatic. The Ile436Lys mutation is characterized by low factor XI activity and antigen, namely is a cross-reaction material negative form. Molecular modeling indicates that the Ile436Lys mutation causes a large conformational change within the 432-442 loop. No relation could be traced among the different families; however, all their ancestors were autochthonous of the same two small towns. Furthermore, no Jewish ancestry could be found. The close geographical area in which all these patients were found and the absence of the same mutation in the general population of the area strongly suggests a founder effect and that the mutation is responsible for the defect. The compound heterozygosis with the Glu 117 stop mutation, common among Jews, was not surprising because of the past strict ties of the Republic of Venice with the Middle East.

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Characterization of seven novel mutations causing factor XI deficiency

Cited by 26 publications

References 24 publications

High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study

High incidence of FXI deficiency in a Spanish town caused by 11 different mutations and the first duplication of F11: Results from the Yecla study

Molecular basis and bleeding manifestations of factor XI deficiency in 11 Turkish families

A cluster of factor XI‐deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy*

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