Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency

Mitchell, Michael J.; Gattens, Michael; Kavaklı, Kaan; Liesner, Ri; Payne, Jeanette; Norton, Miranda; Austin, Steven

doi:10.1097/mbc.0000000000000787

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…Therefore, we may preliminarily conclude that these two sequence variant sites have a dose-effect relationship and cause FX deficiency. Similar cases of compound heterozygous mutations have been also reported by many studies [14,[38][39][40][41][42]. Our research reported two novel unreported mutations for the first time, and conducted in vitro functional studies on them to find potential pathogenic mechanism also.…”

Section: Discussionsupporting

confidence: 84%

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Feng

Tang

et al. 2021

Genes

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Background: Congenital coagulation factor X (FX) deficiency is a rare bleeding disorder with an incidence of one in one million caused by mutations in the FX-coding gene(F10), leading to abnormal coagulation activity and a tendency for severe hemorrhage. Therefore, identifying mutations in FX is important for diagnosing congenital FX deficiency. Results: Genetic analysis of the proband identified two single-base substitutions: c.794T > C: p.Ile265Thr and c.865 + 5G > A: IVS7 + 5G > A. His FX activity and antigen levels were < 1% and 49.7%, respectively; aPTT and PT were prolonged to 65.3 and 80.5 s, respectively. Bioinformatics analysis predicted the two novel variants to be pathogenic. In-vitro expression study of the missense mutation c.794T > C: p.Ile265Thr showed normal synthesis and secretion. Activation of FXs by RVV, FVII/TF, and FVIII/FIX all showed no obvious difference between the variant and the reference. However, clotting activity by PT and aPTT assays and activity of thrombin generation in a TGA assay all indicated reduced activity of the mutant FX-Ile265Thr compared to FX-WT. Minigene assay showed a normal splicing mode c.865 + 5G > A: IVS7 + 5G > A, which is inconsistent with clinical phenotype. Conclusions: The heterozygous variants c.794T > C: p.Ile265Thr or c.865 + 5G > A: IVS7 + 5G > A indicate mild FX deficiency, but the compound heterozygous mutation of the two causes severe congenital FX deficiency. Genetic analysis of these two mutations may help characterize the bleeding tendency and confirm congenital FX deficiency. In-vitro expression and functional study showed that the low activity of the mutant FX-Ile265Thr is caused by decrease in its enzyme activity rather than self-activation. The minigene assay help us explore possible mechanisms of the splicing mutation. However, more in-depth mechanism research is needed in the future.

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Section: Discussionsupporting

confidence: 84%

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Feng

Tang

et al. 2021

Genes

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“…Individuals with a severe bleeding phenotype generally have homozygous or compound heterozygous mutations in the F10 gene. Heterozygous individuals may be asymptomatic or have mild or moderate disease 7–9 . Most identified F10 mutations are missense mutations, although insertions, deletions and splicing mutations are also observed 9–11 .…”

Section: Introductionmentioning

confidence: 99%

“…Heterozygous individuals may be asymptomatic or have mild or moderate disease. [7][8][9] Most identified F10 mutations are missense mutations, although insertions, deletions and splicing mutations are also observed. [9][10][11] Genetic variants of the F10 gene can be found online.…”

Section: Introductionmentioning

confidence: 99%

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Plasma‐derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency

Escobar,

Kavakli

2023

Haemophilia

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IntroductionHereditary factor X (FX) deficiency (HFXD) is an autosomal recessive rare bleeding disorder that leads to defects in the FX protein. Depending on the degree of deficiency, patients may be at risk of life‐threatening bleeding episodes. Historical treatments for FX deficiency include prothrombin complex concentrates, which can increase the risk of thrombosis, and fresh frozen plasma, which can cause volume overload and transfusion reactions. Plasma‐derived FX (pdFX), a single‐factor, high‐purity, high‐potency human FX treatment, was approved in 2015 in the United States and in 2016 in Europe for on‐demand treatment and prophylaxis of bleeding episodes and perioperative management of patients with HFXD.MethodsFive studies that examined the use of pdFX in patients with mild (plasma FX activity [FX:C] ≥5 IU/dL), moderate (FX:C ≥1 and <5 IU/dL), or severe (FX:C < 1 IU/dL) HFXD were reviewed: TEN01, TEN02 and TEN03 were prospective, open‐label, multicentre, nonrandomised studies, and TEN05 and TEN06 were multicentre retrospective studies.ResultsWhen used as an on‐demand treatment, pdFX was judged by investigators to be successful in treating 41/42 (97.6%), 2/3 (66.6%) and 79/79 (100%) bleeds in TEN01, TEN02 and TEN05, respectively. When used prophylactically, pdFX was judged ‘excellent’ for the prevention of bleeds in nine (100%) and eight (100%) patients in TEN02 and TEN05, respectively. Perioperative treatment and pharmacokinetics were also assessed. pdFX was safe and well tolerated.ConclusionsTogether, these studies support the use of pdFX for on‐demand treatment of bleeding, routine prophylaxis, and perioperative management of bleeding in patients with HFXD.

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“…The inherited type is an autosomal recessive type, which mainly occurs due to nonsense mutations in the F10 gene, 4,6 which is why it is sometimes known as F10 deficiency. It is mostly seen in nations with a high percentage of consanguineous marriage 7 .…”

Section: Introductionmentioning

confidence: 99%

“I have been refused to be treated by three dentists”: Barriers to patient care

Abed

Abuljadayel

2020

Special Care in Dentistry

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Genotype analysis and identification of novel mutations in a multicentre cohort of patients with hereditary factor X deficiency

Cited by 8 publications

References 27 publications

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Characterization of a Missense Mutation in the Catalytic Domain and a Splicing Mutation of Coagulation Factor X Compound Heterozygous in a Chinese Pedigree

Plasma‐derived human factor X concentrate for the treatment of patients with hereditary factor X deficiency

“I have been refused to be treated by three dentists”: Barriers to patient care

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