<i>F9</i> mutations causing deletions beyond the serine protease domain confer higher risk for inhibitor development in hemophilia B

Liu, Guoqing; Sun, Jie; Li, Zekun; Chen, Zhenping; Wu, Wenman; Wu, Runhui

doi:10.1182/blood.2022017871

Cited by 3 publications

(1 citation statement)

References 13 publications

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“…Cases 1 and 2 belonged to the severe HB patients cohort admitted to the Beijing Children's Hospital from 2015 to 2022, who were previously reported to have a deletion spanning all eight exons of the F9 gene. 23 Cases 3, 4, and 5 belonged to the VTE patients cohort registered in Shanghai Ruijin Hospital from 2017 to 2023. They were identified with additional copies of the complete F9 gene through our Hemostasis and Thrombosis Gene Panel analysis.…”

Section: Methodsmentioning

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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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: Methodsmentioning

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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Study on the Mutation of FⅨ Gene in 31 Patients with Type B Hemophilia

Liu,

Guo,

Chen

et al. 2024

Clin Appl Thromb Hemost

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Hemophilia B (HB) is an inherited bleeding disorder caused by defects in the FⅨ gene, leading to severe coagulation dysfunction. This study designed eight pairs of primers covering eight exons of the FⅨ gene and used PCR and DNA sequencing to detect FⅨ gene mutations in 31 HB patients. Sequencing results were compared with normal sequences using Chromas software on Blast to identify mutation sites. Findings revealed the CpG dinucleotide region as a mutation hotspot and the 192nd nucleotide (FⅨ192) as a dinucleotide polymorphism site in the Chinese population. Pathogenic mutations included point mutations, deletions, insertions, and mutations affecting amino acids or splicing sites. For cases with only polymorphic sites, further exon sequencing is needed. This study adds new mutation data to the global HB database, supports research on racial differences in FⅨ gene mutations, and contributes to domestic HB statistics. The results aid in understanding the FⅨ gene's role in coagulation, elucidating HB pathogenesis, and providing a basis for future gene therapy.

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Recent Advances in Genetic and Non-Genetic Factors Related to the Development of Hemophilia Inhibitors

李

2024

ACM

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F9 mutations causing deletions beyond the serine protease domain confer higher risk for inhibitor development in hemophilia B

Cited by 3 publications

References 13 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

Study on the Mutation of FⅨ Gene in 31 Patients with Type B Hemophilia

Recent Advances in Genetic and Non-Genetic Factors Related to the Development of Hemophilia Inhibitors

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