Severe factor XI deficiency in a Korean woman with a novel missense mutation (Val498Met) and duplication G mutation in exon 13 of the F11 gene

Abstract

Hereditary factor XI (FXI) deficiency is a rare bleeding disorder inherited in an autosomal recessive manner. The genetic background of FXI deficiency is the mutations in the F11 gene on the chromosome band 4q35. The prevalence is known to be particularly high in Ashkenazi Jews with well documented recurrent mutations; however, founder mutations in F11 have also been reported in non-Jewish patients. In this report, we describe a Korean patient with severe FXI deficiency whose causative mutations were identified by molecular genetic tests. The patient was a 33-year-old pregnant woman. Routine gynecologic workup revealed prolonged activated partial thromboplastin time. Her FXI level was severely decreased at 1% (reference range, 60-140%). Direct sequencing analysis of the F11 gene was performed to identify the causative mutations. The patient was shown to have two different mutations, c.1546 G>A (Val498Met) and c.1560dupG (Tyr503ValfsX32) in the F11 gene. Val498Met is a novel missense mutation, and the Tyr503ValfsX32 mutation was recently reported in a Japanese patient. Both mutations occurred in the exon 13 of F11 and were believed to disrupt the catalytic domain of the FXI protein, leading to severe FXI deficiency. To the best of our knowledge, this is the first genetically confirmed case of severe FXI deficiency in Korea, and more cases are needed to find any signature of founder effect in the Korean population and its potential relationship with other Asian populations.

Cys482Trp Missense Mutation in the Coagulation Factor XI Gene (F11) in a Korean Patient with Factor XI Deficiency

“…Their study showed that 57.1% of patients had mutations in exons 7 and 8, with the detection rate increasing to 71.4% when exon 13 was included, and to 80.1% when exon 11 was also included. In addition, all the other reported cases where the molecular bases of the FXI deficiency were confirmed in the Korean patients were found to be mutations affecting either exon 7 [18] or exon 13 [16, 17]. Thus, these findings strongly indicate that identification of causative mutations in the Korean patients with FXI deficiency should involve initial screening of mutations in exons 7, 8, 11, and 13 by sequencing.…”

“…Only 17 cases of FXI deficiency (including the present case) have been confirmed by molecular and genetic testing in Korea [14, 16, 17, 18] (Table 1). Therefore, further testing and discovery of molecular lesions in the F11 gene in the Korean patients with FXI deficiency is needed to gain better understanding of founder mutations that are specific to this population.…”

A Novel Missense Mutation Asp506Gly in Exon 13 of the F11 Gene in an Asymptomatic Korean Woman with Mild Factor XI Deficiency

“…In Korea, hereditary FXI deficiency is rare, and only 8 cases have been reported [7-11]. A history of spontaneous bleeding has not been reported even in patients with severe deficiency, except in 1 case with intermittent nasal bleeding, which was easily controlled.…”

“…In most of the cases, the diagnosis of FXI deficiency was made on the basis of coagulation test results without molecular genetic study. Only 1 case, in which severe deficiency was observed due to compound heterozygous mutations (Val498Met and Tyr503ValfsX32) of the F11 gene, has been genetically confirmed to date [11]. The patient showed no spontaneous or postoperative bleeding despite the severely decreased FXI activity (1%).…”

“…Only 8 cases of FXI deficiency have been reported in Korea, of which only 1 case has been genetically confirmed to be a case of severe FXI deficiency [7-11]. To the best of our knowledge, this is the first genetically confirmed case of mild FXI deficiency in Korea.…”