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

Abstract

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.

Type I mutation in the F11 gene is a third ancestral mutation which causes factor XI deficiency in Ashkenazi Jews

“…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 , the UK , northern Italy and Korea .…”

Congenital Factor XI Deficiency: An Update

“…85 In patients belonging to different ethnic groups, a significantly higher level of allelic heterogeneity has been reported. Remarkable exceptions are represented by some "closed populations" harboring mutations compatible with a founder effect: Cys38Arg in French Basques, 39 Gln88Stop in French families from Nantes, 18 Cys128Stop in Britons, 38 Ile436Lys in Northeastern Italy, 86 and Q263X in Korean patients. 87…”

The spectrum of factor XI deficiency in Italy

“…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.…”