Novel missense mutations in two patients with factor XI deficiency (Val271Leu and Tyr351Ser) and one patient with combined factor XI and factor IX deficiency (Phe349Val)

Jayandharan, Giridhara R.; Shaji, R. V.; Nair, Sukesh C.; Chandy, Mammen; Srivastava, Alok

doi:10.1111/j.1538-7836.2005.01230.x

Cited by 13 publications

(13 citation statements)

References 17 publications

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“…The most frequent one seems to be the Gly 460 Arg, described at the homozygous level in at least three families and which appears similar to the mutation here reported (17, 35, 36). Both compound heterozygotes and heterozygotes have also been investigated.…”

Section: Discussionsupporting

confidence: 85%

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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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Section: Discussionsupporting

confidence: 85%

“…The mutation present in the propositi involves exon 12 of the catalytic domain. There are several other mutations controlled by exon 12, for example, those reported in Refs (12,16,17,33,34,35,36,37), but the least is not complete.…”

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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“…Similar arguments help explain the frequent reports of combined FVIII and FXI deficiency [27][28][29] and combined FIX and FXI deficiency [12,30] compared with combined factor VIII and IX deficiency [31], combined FV and FVII deficiency [11,32] and combined FVII and FVIII deficiency [33] which are predicted to be very rare as co-incidentally inherited disorders. Historical descriptions of the disorders corresponding to FMCFD II, IV, V and VI proposed by Soff and Levin, are reviewed in detail by these authors [1,2].…”

Section: Fmcfds Arising From Co-inheritance Of Independent Coagulatiosupporting

confidence: 56%

“…In this case, the cumulative effect of both mild deficiencies may prolong the APTT sufficiently to provoke further investigation with coagulation factor activity assays [22]. This potential ascertainment bias may explain the apparent over-representation of FMCFDs that include mild FXI deficiency and mild VWD, haemophilia A and haemophilia B in UK Haemophilia Centre registry data (Table 3) and in published case reports [12,[14][15][16][17][27][28][29][30].…”

Section: Clinical and Laboratory Aspects Of The Fmcfdsmentioning

confidence: 99%

Familial multiple coagulation factor deficiencies – chance associations and distinct clinical disorders

Robson

Mumford

2009

Haemophilia

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The familial multiple coagulation factor deficiencies (FMCFDs) are a group of rare haemostatic disorders of genetic origin in which there is reduced plasma activity of more than one coagulation factor. FMCFDs may arise from co-incidental inheritance of separate coagulation factor deficiencies or from a single genetic or cytogenetic defect. All the FMCFDs present significant challenges in diagnosis and management yet there is little systematic evidence with which to guide clinical practice. This review summarizes the historical literature that describes the FMCFDs and introduces a refined classification of these disorders. The clinical and laboratory characteristics of the most common FMCFDs are considered in detail.

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“…Furthermore, rs2289252 was associated with miscarriages, decreased APTT and high FXI levels. (Ventura et al 2000;Zivelin et al 2002;Zadra et al 2004;Zadra et al 2008;Kim et al 2012;Bicocchi et al 2013) rs5970 c.1191T > C p.Gly397¼ Exon 11 VTE N (Gerdes et al 2004) N (Zivelin et al 2002;de Moerloose et al 2004;Zadra et al 2004;Bezak et al 2005;Jayandharan et al 2005;Zadra et al 2008;Kim et al 2012;Bicocchi et al 2013), (Martincic et al 1998) This SNV is located in intron 12 (c.1481-188) and the result of a C > T substitution. Eight other SNVs, including rs1593, rs3822057, rs925451, rs4253430, rs4253414, rs4253399, rs3733403 and rs3822056 also showed an association with venous thrombosis.…”

Section: Non-coding Variantsmentioning

confidence: 99%

Factor 11 single-nucleotide variants in women with heavy menstrual bleeding

Wiewel-Verschueren

Mulder

Meijer

et al. 2017

Journal of Obstetrics and Gynaecology

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In a previous study it was shown that lower factor XI (FXI) levels in women with heavy menstrual bleeding (HMB). Our aim was to determine the single-nucleotide variants (SNVs) in the F11 gene in women with HMB. In addition, an extensive literature search was performed to determine the clinical significance of each SNV. Patients referred for HMB (PBAC-score >100) were included. With direct sequencing analysis of all 15 exons and flanking introns of the F11 gene, 29 different non-structural SNVs were detected in 49 patients with HMB. Interestingly, most of these SNVs have previously been associated with venous thrombosis instead of bleeding. These findings have not helped to elucidate the molecular basis of HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB. IMPACT STATEMENTWomen with mild deficiencies of factor XI (FXI) (< 70%) are prone to excessive bleeding during menstruation. Bleeding manifestations are not well correlated with plasma FXI levels and bleeding episodes can vary widely among patients with similar low FXI levels. In a previous study we showed that women with heavy menstrual bleeding (HMB) had normal, but on average, lower levels of FXI than controls. In light of these findings, we performed F11 gene analysis to determine the single-nucleotide variants (SNVs) in women with HMB and performed an extensive literature search to determine the clinical significance of each SNV. By direct sequencing analysis of the F11 gene we found 29 different non-structural SNVs in 49 women with heavy menstrual bleeding. Remarkably, a number of these SNVs have previously been implicated in thrombosis. These findings have not helped to elucidate the molecular basis of lower FXI levels in HMB. They also question the specificity of previously reported F11 variations in patients with thrombosis. More studies are needed to explain the lower FXI levels seen in patients with HMB.

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Novel missense mutations in two patients with factor XI deficiency (Val271Leu and Tyr351Ser) and one patient with combined factor XI and factor IX deficiency (Phe349Val)

Cited by 13 publications

References 17 publications

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

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

Familial multiple coagulation factor deficiencies – chance associations and distinct clinical disorders

Factor 11 single-nucleotide variants in women with heavy menstrual bleeding

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