Genetic analysis in Factor XI deficient patients from central China: Identification of one novel and seven recurrent mutations

SummaryConstitutional 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.

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The Molecular Genetic Analysis of Coagulation Factor XI (FXI) Deficiency in Two Chinese Patients

Blood ◽

10.1182/blood-2018-99-118232 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5033-5033

Author(s):

Rong-Fu Zhou ◽

Qian Li ◽

Min Zhou

Keyword(s):

Genetic Analysis ◽

Conflicts Of Interest ◽

Coagulation Factor ◽

Chinese Patients ◽

Compound Heterozygous ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Software Analysis ◽

Prolonged Aptt ◽

Compound Heterozygous Mutations

Abstract Objective: To investigate the molecular pathogenesis of two coagulation factor XI (FXI) deficiency patients. Methods: The diagnosis was validated by coagulant assays: APTT and correct test, PT, INR and coagulation factors activities. Coagulation factor activity were tested with clotting assay. The patients' DNA were extracted and all exons and flanking sequences of FXI gene were amplified using PCR. After purified, the products were sent for sequencing directly, the mutations were detected by comparing with wild sequences and analyzed using some bioinformatics software. Results: The two patients were diagnosed as coagulation factor XI deficiency due to prolonged APTT and low activities of coagulation factor FXI. The results of APTT, FXI:C was 88.1s, 1.1% and 107.1s, 3.8% , respectively. Genetic analysis found that compound heterozygous mutations g.1251-1G > A and g.1271delT in the first patient and the sequencing results of TA plasmid clones showed that the two mutations were located on different single strands of chromosomes. Double heterozygous mutations g.1070A >G and g.1446C > G were detected in the second patient, resulting in Lys357Arg and Cys482Stop. Software analysis indicated the mutations probably brought amino acid sequence changed, protein features affected and splice site changed. Conclusion: Compound heterozygous mutations g.1251-1G > A, g.1271delT and g.1070A > G , g.1446C > G had been identified in two coagulation factor XI deficiency patients, which might be the cause of their prolonged APTT and low FXI:C. To the best of our knowledge, the four mutations are reported for the first time in the literature. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Molecular Genetic Analysis of Factor XI Deficiency: Identification of Five Novel Gene Alterations and the Origin of Type II Mutation in Portuguese Families

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614125 ◽

2000 ◽

Vol 84 (11) ◽

pp. 833-840 ◽

Cited By ~ 20

Author(s):

Célia Ventura ◽

Ana I. Santos ◽

Alice Tavares ◽

Teresa Gago ◽

João Lavinha ◽

...

Keyword(s):

Genetic Analysis ◽

Molecular Genetic ◽

Coagulation Factor ◽

Molecular Genetic Analysis ◽

Null Alleles ◽

Type Ii ◽

Factor Xi ◽

Factor Xi Deficiency ◽

Premature Termination Codons ◽

Gene Alterations

SummaryCoagulation factor XI (FXI) deficiency is an inherited autosomal recessive mild bleeding disorder. In this study, we report the molecular genetic analysis of FXI deficiency in six unrelated families of Portuguese origin. The Jewish type II mutation was found in two families, of seemingly Portuguese origin. Haplotype analysis in these families demonstrated that this mutation is of Jewish origin. In the remaining families, five novel FXI mutations have been identified. Two of these mutations (FXI IVS K -10T→A and FXI 1026G→T, cd 324) affect the FXI pre-mRNA splicing. A further two (FXI 307 ins AAGCAAT, cd 85 and FXI 1072 del A, cd 340) introduce frameshifts leading to premature termination codons. The FXI splicing mutation, 1026G→T cd 324, was found in compound heterozygosity with missense mutation FXI K518N. Analysis of the FXI mRNA from the latter genotype demonstrated new donor splice site usage. All reported mutations most likely result in functional null-alleles. In addition, three novel polymorphisms have been identified: at nt -138 in intron A, at codon D125 in exon 5 and at codon T249 in exon 8.

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