OBJECTIVE: To investigate a family with hereditary coagulation factor XI (FXI) deficiency, identify its possible genetic etiology, analyze the bleeding risk of the proband, and provide a blood transfusion regimen. METHODS: The blood samples from the family members were collected, and the coagulation parameters of the proband and her family members were detected. Whole-exome sequencing was performed on the blood samples of the proband to identify gene variants, and validate the variants in the family using Sanger sequencing. Bioinformatics softwares were used to analyze the conservation of amino acid variant sites and the impact of the variations on protein function. The pathogenicity of the variant sites was analyzed according to the genetic variation classification criteria and guidelines of the American College of Medical Genetics and Genomics (ACMG). Thromboelastography (TEG) was used to assess the coagulation function of the family members and evaluate the transfusion regimen and its efficacy in the proband. RESULTS: The activated partial thromboplastin time (APTT) of the proband was significantly prolonged to 96.7 seconds, and FXI activity (FXI: C) and FXI antigen (FXI: Ag) decreased to 1.3% and 1%, respectively, both of which were extremely reduced. The FXI: C of the proband's father was also significantly lower than the normal value. The TEG results showed that the coagulation function of the proband was reduced, while the coagulation function of other family members was normal. The F11 gene of the proband exhibited compound heterozygous variants of c.738G>A (p.Trp246 *) and c.1288G>A (p.Ala430Thr). The proband's father carried a heterozygous missense variant of c.1288G>A (p.Ala430Thr), while her mother, her eldest daughter, and her youngest daughter carried a heterozygous nonsense variant of c.738G>A (p.Trp246 *). According to the ACMG genetic variation classification criteria and guidelines, c.738G>A (p.Trp246 *) is classified as a pathogenic variant (PVS1+PS3-Moderate+PP4), and c.1288G>A (p.Ala430Thr) is classified as a possible pathogenic variant (PS3-Moderate+PM1+PM3_Srong+PP4). p.Trp246 and p.Ala430 are highly conserved across different species. Swiss PdbViewer software analysis showed that p.Ala430Thr variant caused a change in the number of hydrogen bonds in FXI protein, affecting protein function. The following transfusion regimen was determined through TEG evaluation in vitro: 600 ml of fresh frozen plasma (FFP) was administered 24 hours before surgery to prevent bleeding. And there was no significant bleeding during or after the surgery. CONCLUSION The heterozygous nonsense variant ofc.738G>A (p.Trp246 *) and the heterozygous missense variant of c.1288G>A (p.Ala430Thr) in the F11 gene are the pathogenic factors of this hereditary FXI deficiency family.
Humans ; Factor XI Deficiency/therapy* ; Factor XI/genetics* ; Blood Transfusion ; Pedigree ; Female ; Male ; Mutation ; Thrombelastography ; Partial Thromboplastin Time ; Blood Coagulation ; Adult

OBJECTIVE: To explore the phenotypic and genotypic characteristics of a Chinese pedigree affected with Hereditary coagulation factor XI (FXI) deficiency. METHODS: A female patient with FXI deficiency and her family members (five individuals from three generations) who presented at Quanzhou First Hospital Affiliated to Fujian Medical University on September 19, 2024 due to diarrhea and fever were selected as study subjects. A retrospective study was conducted to collect the patients' clinical data. Peripheral venous blood samples were collected from the patient and her family members. Genomic DNA was extracted, followed by sequencing of all exons and flanking sequences of the F11 gene. Candidate variants were validated by Sanger sequencing of the family members, and their pathogenicity was classified according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of Quanzhou First Hospital [Approval No.: Quanyi Lun (2024) K281]. RESULTS: The patient exhibited significantly prolonged activated partial thromboplastin time (APTT) of 80.9 seconds, while FXI activity (FXI:C) and FXI antigen (FXI:Ag) levels were extremely low (2% and 3%, respectively). Genetic analysis revealed that the proband harbored homozygous c.896C>G (p.Thr299Ser) missense variant in exon 9 of the F11 gene, for which her son was heterozygous. The variant was located in a highly conserved domain. Although Mutation Taster predicted it as a polymorphism, SIFT, PolyPhen-2, and LRT analyses suggested it to be likely pathogenic. Protein modeling indicated that the p.Thr299Ser variant may alter the hydrogen bonds between amino acids, thereby affecting the structure and function of the FXI protein. According to the ACMG guidelines, c.896C>G was rated as a likely pathogenic variant (PM1+PM2_Supporting+PP1_Strong+PP3+PP4). CONCLUSION The c.896C>G (p.Thr299Ser) missense variant of the F11 gene probably underlay the FXI deficiency in this pedigree. Above finding has enriched the mutational spectrum of the F11 gene and provided a basis for genetic counseling and prenatal diagnosis for this family.
Adult ; Female ; Humans ; Male ; Middle Aged ; China/ethnology* ; Factor XI/chemistry* ; Factor XI Deficiency/genetics* ; Homozygote ; Pedigree ; Retrospective Studies ; East Asian People/genetics*

OBJECTIVE: To explore the molecular pathogenesis of a Chinese pedigree affected with Hereditary coagulation factor Ⅺ (FⅪ) deficiency due to variants of the F11 gene. METHODS: A male proband with Hereditary coagulation factor Ⅺ deficiency who was admitted to the First Affiliated Hospital of Wenzhou Medical University due to urinary calculi on November 30, 2020 and his family members (7 individuals from 3 generations in total) were selected as the study subjects. Clinical data of the proband were collected, and relevant coagulation indices of the proband and his family members were determined. Genomic DNA of peripheral blood samples was extracted for PCR amplification. All exons, flanking sequences, and 5' and 3' untranslated regions of the F11 gene of the proband were analyzed by direct sequencing. And the corresponding sites were subjected to sequencing in other family members. The conservation of amino acid variation sites was analyzed by bioinformatic software, and the effect of the variant on the protein function was analyzed. Variants were graded based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The proband was a 36-year-old male. His activated partial thromboplastin time (APTT) was 89.2s, which was significantly prolonged. The FⅪ activity (FⅪ:C) and FⅪ antigen (FⅪ:Ag) were 2.0% and 3.5%, respectively, which were extremely reduced. Both the proband and his sister were found to harbor compound heterozygous variants of the F11 gene, including a c.689G>T (p.Cys230Phe) missense variant in exon 7 from their father and a c.1556G>A (p.Trp519*) nonsense variant in exon 13 from their mother. Conservation analysis indicated the Cys230 site to be highly conserved. The c.1556G>A (p.Trp519*) variant was known to be pathogenic, whilst the c.689G>T variant was classified as likely pathogenic (PM2+PM5+PP1+PP3+PP4) based on the ACMG guidelines. CONCLUSION The c.689G>T and c.1556G>A compound heterozygous variants of the F11 gene probably underlay the pathogenesis of FⅪ deficiency in this pedigree.
Adult ; Humans ; Male ; 3' Untranslated Regions ; East Asian People ; Factor XI/genetics* ; Factor XI Deficiency/genetics* ; Partial Thromboplastin Time ; Pedigree

OBJECTIVE: To analyze the clinical phenotype and genetic basis for a Chinese pedigree affected with coagulation factor XI (FXI) deficiency. METHODS: Activated partial thromboplastin time (APTT) and other blood coagulation factors, and activities of FXI:C and other relevant coagulation factors for a large Chinese pedigree including 6 patients from 3 generations were determined on a Stago automatic coagulometer. The FXI:Ag was determined with an ELISA method. All exons and flanking regions of the F11 gene were subjected to Sanger sequencing. ClustalX-2.1-win software was used to analyze the conservation of amino acids. Pathogenicity of the variants was predicted with online bioinformatics software including Mutation Taster and Swiss-Pdb Viewer. RESULTS: The APTT of the proband was prolonged to 94.2 s. The FXI:C and FXI:Ag were decreased to 1% and 1.3%, respectively. The APTT of her father, mother, son and daughter was 42.1 s, 43.0 s, 42.5 s and 41.0 s, respectively. The FXI:C and FXI:Ag of them were almost halved compared with the normal values. The APTT, FXI:C and FXI:Ag of her husband were all normal. Genetic testing revealed that the proband has carried a heterozygous missense c.1103G>A (p.Gly350Glu) variant in exon 10 and a heterozygous missense c.1556G>A (p.Trp501stop) variant in exon 13 of the F11 gene. The father and daughter were heterozygous for the c.1103G>A variant, whilst the mother and son were heterozygous for the c.1556G>A variant. Both Gly350 and Trp501 are highly conserved among homologous species, and both variants were predicted to be "disease causing" by Mutation Taster. Protein modeling indicated there are two hydrogen bonds between Gly350 and Phe312 in the wild-type, while the p.Gly350Glu variant may add a hydrogen bond to Glu and Tyr351 and create steric resistance between the two, both may affect the structure and stability of protein. CONCLUSION The c.1103G>A and c.1556G>A compound heterozygous variants probably underlay the pathogenesis of congenital FXI deficiency in this pedigree.
Exons/genetics* ; Factor XI/genetics* ; Factor XI Deficiency/genetics* ; Female ; Heterozygote ; Humans ; Male ; Mutation ; Pedigree

OBJECTIVE: To analyze the phenotype and genetic basis for a pedigree affected with hereditary coagulation factor XI deficiency. METHODS: Activated partial thromboplastin time (APTT), prothrombin time (PT), fibrinogen (FIB), FXI activity (FXI:C) and the antigen of FXI (FXI:Ag) were determined for the proband and members from his pedigree. Sanger sequencing was used to analyze all exons, exon-intronic boundaries, as well as the 5'- and 3'- untranslated regions of the F11 gene. Suspected variants were verified in her family members and confirmed by reverse sequencing. The impact of the variants on the protein function was predicted by using PolyPhen-2 and SIFT software. The protein structure and amino acid interaction were analyzed by using Swiss-PdbViewer. RESULTS: The APTT, FXI:C and FXI:Ag of the proband and her sister were significantly reduced to 73.0 s, 10.0%, 15.0% and 87.1 s, 2.0% and 11.5%, respectively. APTT of some family members was slightly prolonged, and FXI:C and FXI:Ag also decreased to various extents. DNA sequencing revealed that the proband and her sister have carried compound heterozygous variants of c.738G>A (p.Trp228stop) and c.938G>T (p.Ser295Ile) respectively in exons 7 and 9 of the F11 gene. Her father, sister and daughter were heterozygous for the c.738G>A (p.Trp228stop) variant, while her mother and nephew were heterozygous for the c.938G>T (p.Ser295Ile). Both PolyPhen-2 and SIFT predicted that the p.Ser295Ile variant is likely to be deleterious and can affect the protein function. Modeling analysis indicated that the p.Ser295Ile variant may lead to disruption of a hydrogen bond, resulting in alteration of protein structure and instability. CONCLUSION The compound heterozygous c.738G>A (p.Trp228stop) and c.938G>T (p.Ser295Ile) variants of the F11 gene probably underlie the decreased FXI level in this pedigree.
Factor XI Deficiency ; genetics ; Female ; Genetic Variation ; Heterozygote ; Humans ; Mutation ; Pedigree

OBJECTIVE: To analyze the phenotype and genetic mutations in a pedigree affected with factor Ⅺ (FⅪ) deficiency. METHODS: Activated partial thromboplastin time (APTT), FⅪ activity (FⅪ:C) and FⅪ antigen (FⅪ:Ag) were determined for the proband and his family members. All exons and exon-intron boundaries of the FⅪ gene of the proband were analyzed by direct sequencing. Suspected mutation was verified in his family members. RESULTS: The proband had APTT of 82.4 s, FⅪ:C of 0.8%, and FⅪ:Ag of <1%. DNA sequencing showed that he has carried c.1033A>T (Lys327X) mutation in exon 10 and c.1325delT (Leu424CysfsX8) mutation in exon 12 of the FⅪ gene. His elder sister, son, daughter, two granddaughters and one grandson were heterozygous carriers of the c.1033A>T mutation, while his older sister and younger brother were heteozygous carriers of the c.1325delT mutation. Analysis using Mutation Taster software showed that both p.Lys327X and p.Leu424CysfsX8 may affect the function of protein and lead to the corresponding disease. CONCLUSION The novel mutations of Lys327X and Leu424CysfsX8 of the the FⅪ gene probably underlie the pathogenesis of congenital coagulation factor Ⅺ deficiency in this pedigree.
Exons ; Factor XI ; genetics ; Factor XI Deficiency ; genetics ; Female ; Heterozygote ; Humans ; Male ; Mutation ; Pedigree

OBJECTIVE: To identify potential mutations of F11 gene in a pedigree affected with hereditary coagulation factor XI (FXI) deficiency and explore its molecular pathogenesis. METHODS: Prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), coagulation factor VIII activity (FVIIIC), coagulation factor IX activity (FIXC), coagulation factor XI activity (FXIC), coagulation factor XII activity (FXIIC) and lupus anticoagulation (LA) of the proband and eight family members were determined. FXI antigen (FXIAg) was determined by enzyme-linked immunosorbent assay (ELISA). For the proband, potential mutations in the exons, flanking introns and 5'-, 3'-untranslated regions of the F11 gene were screened by direct DNA sequencing. The results were confirmed by reverse sequencing. Suspected mutations were detected in other family members. ClustalX-2.1-win and four online bioinformatic tools (PolyPhen-2, PROVEAN, SIFT, and Mutation Taster) were used to study the conservation and possible impact of the mutations. The structure of the mutational sites was processed with Swiss-PdbViewer. RESULTS: The propositus had prolonged APTT (69.6 s), whose FXIC and FXIAg were reduced to 6.0% and 10.7%, respectively. Her mother, elder sister, one younger sister, little brother, daughter and son showed slightly prolonged APTT and moderate FXIC and FXIAg levels. Gene sequencing revealed that the propositus carried a heterozygous nonsense mutation c.738G>A (p.Trp228stop) in exon 7 and a heterozygous mutation c.1556G>C (p.Trp501Ser) in exon 13. Her mother, elder sister and daughter were heterozygous for the p.Trp228stop mutation, while one younger sister and little brother and son were heterozygous for p.Trp501Ser. Her husband and the youngest sister were of the wild type. Phylogenetic analysis suggested that Trp501 was highly conserved among all homologous species. The p.Trp501Ser was predicted to be "probably damaging","deleterious", "affect protein function" and "disease causing" corresponding to PolyPhen-2, PROVEAN, SIFT and Mutation Taster. Model analysis demonstrated that the non-polar Trp501 has two benzene rings, forming a hydrogen bond with Gln512 in the wild type. Once substituted by Ser501, the side chain may form another hydrogen bond with the benzene of His396. This may affect the normal space conformation and stability of FXI protein. CONCLUSION The compound heterozygous mutations of the F11 gene probably accounted for the low FXI concentration in this pedigree.
Factor XI ; genetics ; Factor XI Deficiency ; genetics ; Female ; Heterozygote ; Humans ; Male ; Mutation ; Pedigree ; Phylogeny

No abstract available.
Adolescent ; Asian Continental Ancestry Group/*genetics ; Child ; Exons ; Factor XI/*genetics ; Factor XI Deficiency/*diagnosis/genetics ; Female ; Genetic Testing ; Genotype ; Heterozygote ; Humans ; Male ; Mutation, Missense ; Partial Thromboplastin Time ; Pedigree ; Republic of Korea ; Sequence Analysis, DNA

Factor XI (FXI) deficiency is a rare autosomal recessive coagulation disorder most commonly found in Ashkenazi and Iraqi Jews, but it is also found in other ethnic groups. It is a trauma or surgery-related bleeding disorder, but spontaneous bleeding is rarely seen. The clinical manifestation of bleeding in FXI deficiency cases is variable and seems to poorly correlate with plasma FXI levels. The molecular pathology of FXI deficiency is mutation in the F11 gene on the chromosome band 4q35. We report a novel mutation of the F11 gene in an 18-year-old asymptomatic Korean woman with mild FXI deficiency. Pre-operative laboratory screen tests for lipoma on her back revealed slightly prolonged activated partial thromboplastin time (45.2 sec; reference range, 23.2-39.4 sec). Her FXI activity (35%) was slightly lower than the normal FXI activity (reference range, 50-150%). Direct sequence analysis of the F11 gene revealed a heterozygous A to G substitution in nucleotide 1517 (c.1517A>G) of exon 13, resulting in the substitution of aspartic acid with glycine in codon 506 (p.Asp506Gly). To the best of our knowledge, the Asp506Gly is a novel missense mutation, and this is the first genetically confirmed case of mild FXI deficiency in Korea.
Adolescent ; Amino Acid Substitution ; Asian Continental Ancestry Group/*genetics ; Base Sequence ; Chromosomes, Human, Pair 4 ; Exons ; Factor XI Deficiency/blood/diagnosis/*genetics ; Female ; Heterozygote ; Humans ; Molecular Sequence Data ; Mutation, Missense ; Protein Structure, Tertiary ; Republic of Korea ; Sequence Analysis, DNA

OBJECTIVETo identify gene defect in a Chinese pedigree of hereditary coagulation factor XI (FXI) deficiency.

METHODSThe peripheral blood samples were collected from the proband and her family members. The plasma PT, APTT, FXI:C and FXI:Ag were assayed. The FXI gene exons and exon-intron boundaries of the proband were amplified by PCR and then sequenced directly. The mRNA of FXI in the peripheral blood was analyzed with RT-PCR.

RESULTSThe proband and some of her family members had prolonged APTT. The plasma FXI:C and FXI:Ag of the proband, her brother and her parents were lower than 10% and 50% of the normal values, respectively. Nucleotide sequence analysis revealed that the proband and her brother had a homozygous mutation of IVS J-4delgttg in FXI gene. The mutation was inherited from her parents who were heterozygotes. The mutation was not found in 60 normal subjects. No FXI mRNA was detected in peripheral blood sample of the proband.

CONCLUSIONThe IVS J-4delgttg is a novel mutation causing FXI deficiency, which may interfere with mRNA splicing.

Adult ; Base Sequence ; DNA Mutational Analysis ; Factor XI ; genetics ; Factor XI Deficiency ; blood ; genetics ; pathology ; Female ; Genotype ; Humans ; Introns ; genetics ; Molecular Sequence Data ; Partial Thromboplastin Time ; Pedigree ; Phenotype ; Point Mutation ; Prothrombin Time ; RNA, Messenger ; genetics ; metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Sequence Deletion