Identification of a novel mutation in a non‐Jewish factor XI deficient kindred

Abstract

Summary. The role of factor XI (FXI) in blood coagulation has been clarified in recent years by descriptions of FXIdeficient patients who are prone to excessive bleeding after haemostatic challenge. We have studied a large kindred of an Italian FXI-deficient patient with a previously undescribed mutation. The propositus, a 68-year-old woman, presented with a cerebral thromboembolic event but had no history of bleeding (FXI activity 1·6 U/dl). A sensitive ELISA failed to detect FXI antigen in the propositus. Sequence analysis of the entire FXI gene revealed a TGG to TGC transversion in codon 228 of exon 7 (FXI-W228C). This missense mutation results in a Trp to Cys substitution within the third apple domain of FXI. We conclude that this novel mutation occurred in a structurally conserved region and may therefore have interfered with either chain folding and secretion or stability of FXI and was responsible for the inherited abnormality seen in this kindred. It is unclear why this kindred does not exhibit a bleeding tendency but it may correlate with a FXI-like antigen and factor IX binding activity expressed on platelets.

Factor XI deficiency presenting in pregnancy: diagnosis and management

“…Sporadic cases have been reported in other ethnic groups 8,9 , with clusters found in the northwest of England 6 and in the Basque country 10 . Novel mutations have also been found in non‐Jewish kindreds 11–13 . Our cases, one of whom was of Ashkenazic background, illustrate the increasing ethnic diversity found in individuals with factor XI deficiency.…”

The spectrum of factor XI deficiency in Italy

“…Twenty‐one additional heterozygotes were identified by genetic analysis in these families. Interestingly, the Trp228Cys mutation was previously reported by an English group in a homozygous Italian patient . All the novel candidate mutations were absent in 100 healthy controls (data not shown).…”

Molecular analysis of severe factor XI deficiency in three Italian patients

“…Genomic DNA was extracted from peripheral blood using a commercial kit (High Pure PCR Template preparation kit; Roche, Mannheim, Germany). Molecular analysis of the whole coding region and the splicing junctions of the F11 gene was performed by direct sequencing analysis in three unrelated Italian patients using already described primers [1]. The results of genetic analysis are described in Table 1.…”