Revisiting the molecular epidemiology of factor XI deficiency: Nine new mutations and an original large 4qTer deletion in western Brittany (France)

Abstract

Constitutional deficiency in factor XI (FXI) is a rare bleeding disorder in the general population, with the exception of Ashkenazi Jews. During the last decade, the detection of FXI-deficient patients has shifted from clinical screening identifying mostly severe bleeders to biological screening combining findings of prolonged activated partial thromboplastin time and FXI coagulation activity (FXI:C) below 50 U/dl. The goal of this study was to determine the molecular basis of FXI deficiency in western Brittany, France. Over the course of four years, we detected 98 FXI-deficient patients through biological screening, and 44 patients agreed to participate in this study corresponding to 25 index cases. We developed an efficient mutation detection strategy (combining direct sequencing and QFM-PCR to search for heterozygous rearrangements in a routine setting) that detected F11 mutations in 24 out of the 25 index cases. An unexpected allelic heterogeneity was found, with 14 different single point mutations being detected, among which nine are new. Moreover, a large heterozygous deletion of the entire F11 gene was detected, and was then further defined using a CGH array as a 4q34.2 telomeric deletion of 7 Mb containing 77 genes. We propose that the observed recurrent mutations may be considered as genetic tags of a population. This study highlights the importance of screening for large deletions in molecular studies of F11 .

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 .…”

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

“…As far as we know, only 5 clusters of patients have been identified with recurrent mutations: the Ashkenazi Jewish population (mutations c.403G>T and c.901T>C), Caucasians in UK (c.438C>A) and in France among Basques (c.166T>C) and in western France (c.316C>T) . Most patients of our study (52% of index cases and 2% of the general population of this town) carried the mutation identified among French Basques and western Brittany . The same haplotype for carriers of this mutation in France and Spain suggests a common origin.…”

“…Development of whole communities from relatively few individuals due to extreme genetic drifts caused by drastic changes in population size, migration and founder effects sustain the high frequency of FXI deficiency in these ethnic groups . However, increasing evidences from epidemiological studies performed in different European and Asian countries suggest that this disorder might have higher incidence than originally believed . A recent study that explored publicly available exome‐based data obtained from >60 000 individuals belonging to different ethnicities found a prevalence of F11 pathogenic mutations responsible for FXI deficiency significantly higher than that reported so far .…”

“…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 .…”

“…Diagnosis of FXI deficiency is usually performed in patients with bleeding that display an elongated activated partial thromboplastin time (APTT), even though there is a poor correlation between FXI levels and bleeding tendency, and APTT is not the best method to diagnose FXI deficiency . These data and recent studies finding a high number of cases with FXI deficiency among non‐Jewish populations question the rarity of this disorder …”