A unique case of thrombophilia: the role of F9 gene duplication and increased factor IX activity in cerebral venous thrombosis

Tan, Turkan Turkut; Parıltay, Erhan; Durmuşalioğlu, Enise Avcı; Işık, Esra; Çoğulu, Özgür; Kavaklı, Kaan; Atik, Tahir

doi:10.1016/j.jtha.2023.06.029

Cited by 3 publications

(3 citation statements)

References 15 publications

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“…46 Recently, Turkut et al reported a 554-kb X-chromosome duplication encompassing the F9 gene, contributing to the elevated FIX activity level and subsequent cerebral venous thrombosis development. 47 Our study provides further evidence that the duplication or triplication of the F9 gene may result in the upregulation of FIX expression, thereby contributing to the manifestation of thrombotic phenotypes. Furthermore, like HB, extra copies of the F9 gene tend to have a greater impact on males than on female carriers.…”

Section: Discussionsupporting

confidence: 54%

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Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Ma,

Li,

Sun

et al. 2023

Thromb Haemost

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Background Factor IX (FIX) plays a critical role in blood coagulation. Complete deletion of F9 results in severe hemophilia B, whereas the clinical implications of complete F9 duplication and triplication remain understudied. Objective To investigate the rearrangement mechanisms underlying complete F9 deletion (cases 1 and 2), duplication (cases 3 and 4), and triplication (case 5), and to explore their association with FIX expression levels and clinical impacts. Methods Plasma FIX levels were detected using antigen and activity assays. CNVplex technology, optical genome mapping, and long-distance polymerase chain reaction were employed to characterize the breakpoints of the chromosomal rearrangements. Results Cases 1 and 2 exhibited FIX activities below 1%. Case 3 displayed FIX activities within the reference range. However, cases 4 and 5 showed a significant increase in FIX activities. Alu-mediated nonallelic homologous recombination was identified as the cause of F9 deletion in case 1; FoSTeS/MMBIR (Fork Stalling and Template Switching/microhomology-mediated break-induced replication) contributed to both F9 deletion and tandem duplication observed in cases 2 and 3; BIR/MMBIR (break-induced replication/microhomology-mediated break-induced replication) mediated by the same pair of low-copy repeats results in similar duplication–triplication/inversion–duplication (DUP–TRP/INV–DUP) rearrangements in cases 4 and 5, leading to complete F9 duplication and triplication, respectively. Conclusion Large deletions involving the F9 gene exhibit no apparent pattern, and the extra-hematologic clinical phenotypes require careful analysis of other genes within the deletion. The impact of complete F9 duplication and triplication on FIX expression might depend on the integrity of the F9 upstream sequence and the specific rearrangement mechanisms. Notably, DUP–TRP/INV–DUP rearrangements significantly elevate FIX activity and are closely associated with thrombotic phenotypes.

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Section: Discussionsupporting

confidence: 54%

“…This may explain why clinical manifestations are predominantly observed in affected males within families exhibiting elevated FIX activity. 6 7 47 …”

Section: Discussionmentioning

confidence: 99%

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Ma,

Li,

Sun

et al. 2023

Thromb Haemost

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“…Patient 20 had similar F9 gene duplication mutation, yet had significantly elevated FIX activity, leading to CVT as detailed in a published article [ 26 ]. Additionally, a Turkish study emphasized that F9 gene duplication mutation and increased FIX activity can lead to unique thrombophilia, ultimately resulting in CVT [ 27 ]. Patient 33 displayed markedly elevated homocysteine level, and subsequent examinations showed elevated blood methionine levels (approximately double the upper limit of normal) alongside normal urinary methylmalonic acid level.…”

Section: Discussionmentioning

confidence: 99%

The genetic risk factors for cerebral venous thrombosis: a case-control study in a Chinese national comprehensive hospital

Wang,

Yao,

Yang

et al. 2024

Thrombosis J

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Background About 13–25% of cerebral venous thrombosis (CVT) cases lack clear etiology, which may be associated with underlying genetic factors. This study aims to investigate genetic factors in CVT patients using whole exome sequencing (WES). Methods Thirty-eight CVT patients hospitalized underwent WES. 977 subjects with WES data from a community cohort study --the Shunyi cohort were as the control group. Using bioinformatics analysis, differential genes with rare damaging variants between two groups were filtered (P < 0.05). KEGG enrichment analysis was performed on the screened genes to identify pathways associated with CVT. Results Through analysis of medical history, routine tests, and imaging examinations, the etiology of 38 patients: 8 cases of antiphospholipid syndrome, 6 cases with hematologic diseases, 3 cases of protein C deficiency, and 2 cases of protein S deficiency. Five cases occurred during pregnancy or puerperium, and 3 cases had a history of oral contraceptive use, and so on. The etiology was unknown in 12 cases (31.6%), and the etiology of 4 patients were further clarified through WES: F9 c.838 + 1_838 + 16del, Hemizygote: F9 EX1-EX7 Dup; CBS c.430G > A, CBS c.949 A > G; F2 c.1787G > A; SERPINC1 c.409-11G > T. Comparing the WES data of two groups, a total of 179 different genes with rare damaging variants were screened (P < 0.05), with 5 genes of interest (JAK2, C3, PROC, PROZ, SERPIND1). Enrichment analysis of the 179 different genes revealed the complement and coagulation pathway and the mitogen activated protein kinases (MAPK) pathway were associated with CVT. Conclusion For CVT patients with unknown etiology, WES could help identify the cause of CVT early, which is of great significance for treatment decisions and prognosis. In addition to the complement and coagulation pathway, MAPK pathway is associated with CVT, potentially related to platelet regulation and inflammatory response.

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A study of recurrent life-threatening thrombosis accompanied with the duplication of the factor IX gene

Wei,

Zhang,

Chen

et al. 2024

Thrombosis J

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Hereditary predisposition play an important role in thrombosis, especially in younger patients. Here we studied a young patient who experienced three different episodes of severe thromboses, some of which were life-threatening (pulmonary artery thrombosis, portal and mesenteric vein thrombosis, and arterial thrombosis of the lower leg). Blood levels of clotting related indicators were assessed. We screened 35 genes linked to thrombosis. We discovered a 756 kb duplication that spanned the F9 gene in region q27.1 of the X chromosome. The repeat includes the full F9 gene, thus, the patient had two functional copies of FIX with the FIX activity 192%. An identical repetition was found in the patient’s mother. Both the patient and his mother had high, but variable, plasma FIX activities that promote coagulation. The patient’s frequent, severe thrombolic events maybe attributed to the duplication of a big portion of the F9 gene and lupus anticoagulant positive.

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A unique case of thrombophilia: the role of F9 gene duplication and increased factor IX activity in cerebral venous thrombosis

Cited by 3 publications

References 15 publications

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

Complete F9 Gene Deletion, Duplication, and Triplication Rearrangements: Implications for Factor IX Expression and Clinical Phenotypes

The genetic risk factors for cerebral venous thrombosis: a case-control study in a Chinese national comprehensive hospital

A study of recurrent life-threatening thrombosis accompanied with the duplication of the factor IX gene

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