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
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DOI：
10.1055/a-2217-9837
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发表时间：
2023-12-26
影响因子：
6.7
通讯作者：
Dai，Jing
中科院分区：
文献类型：
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作者：
Ma，Yuxin;Li，Yang;Dai，Jing
背景因子 IX (FIX) 在血液凝固中起着至关重要的作用。 F9完全缺失可导致严重B型血友病，而F9完全重复和三倍体的临床意义仍有待研究。 目的 探讨F9完全缺失（病例1和2）、重复（病例3和4）和三倍体（病例5）的重排机制，并探讨其与FIX表达水平和临床影响的关系。方法检测血浆FIX水平 使用抗原和活性测定。采用CNVplex技术、光学基因组图谱和长距离聚合酶链式反应来表征染色体重排的断点。结果案例1和案例2的FIX活性低于1%。案例 3 显示 FIX 活动在参考范围内。然而，案例 4 和 5 显示 FIX 活性显着增加。 Alu介导的非等位基因同源重组被确定为病例1中F9缺失的原因； FoSTeS/MMBIR（叉停顿和模板转换/微同源介导的断裂诱导复制）导致案例 2 和案例 3 中观察到的 F9 缺失和串联复制；由同一对低拷贝重复序列介导的 BIR/MMBIR（断裂诱导复制/微同源性介导的断裂诱导复制）导致案例 4 和 5 中类似的重复-三倍/倒位-重复 (DUP-TRP/INV-DUP) 重排，分别导致完全的 F9 重复和三倍体。结论涉及 F9 基因的大缺失 没有表现出明显的模式，并且血液学外的临床表型需要仔细分析缺失内的其他基因。完整的 F9 重复和三倍对 FIX 表达的影响可能取决于 F9 上游序列的完整性和特定的重排机制。值得注意的是，DUP-TRP/INV-DUP 重排显着提高了 FIX 活性，并且与血栓表型密切相关。
BackgroundFactor IX (FIX) plays a critical role in blood coagulation. Complete deletion ofF9results in severe hemophilia B, whereas the clinical implications of completeF9duplication and triplication remain understudied.ObjectiveTo investigate the rearrangement mechanisms underlying completeF9deletion (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.MethodsPlasma 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.ResultsCases 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 ofF9deletion in case 1; FoSTeS/MMBIR (Fork Stalling and Template Switching/microhomology-mediated break-induced replication) contributed to bothF9deletion 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 completeF9duplication and triplication, respectively.ConclusionLarge deletions involving theF9gene exhibit no apparent pattern, and the extra-hematologic clinical phenotypes require careful analysis of other genes within the deletion. The impact of completeF9duplication and triplication on FIX expression might depend on the integrity of theF9upstream sequence and the specific rearrangement mechanisms. Notably, DUP–TRP/INV–DUP rearrangements significantly elevate FIX activity and are closely associated with thrombotic phenotypes.