(TTTCA)exp Drives the Genotype-Phenotype Correlation and Genetic Anticipation in FCMTE1.

IF 7.4 1区医学 Q1 CLINICAL NEUROLOGY Movement Disorders Pub Date : 2024-11-21 DOI:10.1002/mds.30057

Xinhui Chen, Bo Wang, Haibin Xia, Haotian Wang, Dehao Yang, Miao Chen, Huijun Yu, Fan Zhang, Yixin Kang, Yiling Chen, Nan Jin, Lebo Wang, Peng Liu, Fei Xie, Aisi Fu, Ben Hu, Zhiyuan Ouyang, Sheng Wu, Yao Ding, Junfeng Ji, Shuang Wang, Wei Luo, Zhidong Cen

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Abstract

Background: The pentanucleotide (TTTCA) repeat expansion (exp) insertion, along with the accompanying (TTTTA)exp, causes familial cortical myoclonic tremor with epilepsy (FCMTE). The genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp are still unclear.

Objective: The aim was to investigate the genotype-phenotype correlations and intergenerational instabilities related to (TTTCA)exp and (TTTTA)exp in FCMTE1.

Methods: We performed targeted long-read sequencing on 77 FCMTE1 patients. After quality control, metrics such as total repeat count, respective (TTTTA)exp and (TTTCA)exp count, and interruptions were assessed in 73 patients. Correlations between metrics and the patients' clinical features, as well as repeat instability during parental transmission, were analyzed.

Results: Among 73 alleles, the average total repeat counts were 848 ± 152 units, with (TTTTA)exp and (TTTCA)exp averaging 498 ± 196 units and 356 ± 110 units, respectively. (TTTCA)exp counts were inversely correlated with the age at onset for cortical tremor (Spearman's rho = -0.348, P = 0.005) and epilepsy (Spearman's rho = -0.424, P = 0.003). A negative correlation was found between (TTTCA)exp counts and relatively moderate seizure pattern with prodrome (odds ratio = 0.988, 95% confidence interval: 0.980-0.995, P = 0.002). During parental transmission, (TTTCA)exp counts increased significantly (P = 0.007), with maternal transmission showing a significantly larger increase compared to paternal transmission (P = 0.013).

Conclusion: The (TTTCA)exp insertion serves as the length-dependent pathogenic component within the two-motif repeat expansion. Its differential expanding nature during parental transmissions is highly associated with the genetic anticipation in FCMTE1. © 2024 International Parkinson and Movement Disorder Society.

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(TTTCA)exp 驱动了 FCMTE1 基因型与表型的相关性和遗传预测。

背景：五核苷酸(TTTCA)重复扩增(exp)插入以及伴随的(TTTTA)exp会导致家族性皮质肌阵挛性震颤伴癫痫(FCMTE)。与（TTTCA）exp 和（TTTTA）exp 相关的基因型-表型相关性和代际不稳定性仍不清楚：目的：研究 FCMTE1 中 (TTTCA)exp 和 (TTTTA)exp 的基因型表型相关性和代际不稳定性：我们对 77 例 FCMTE1 患者进行了靶向长读程测序。方法：我们对 77 例 FCMTE1 患者进行了靶向长读数测序。经过质量控制后，对 73 例患者的总重复次数、各自的 (TTTTA)exp 和 (TTTCA)exp 次数以及中断次数等指标进行了评估。分析了指标与患者临床特征之间的相关性，以及亲代传播过程中重复的不稳定性：结果：在 73 个等位基因中，平均总重复次数为 848 ± 152 个单位，(TTTTA)exp 和 (TTTCA)exp 平均分别为 498 ± 196 个单位和 356 ± 110 个单位。(TTTCA)exp 计数与皮质震颤（Spearman's rho = -0.348，P = 0.005）和癫痫（Spearman's rho = -0.424，P = 0.003）的发病年龄成反比。研究发现，(TTTCA)exp 计数与前驱症状的相对中度癫痫发作模式之间存在负相关（几率比 = 0.988，95% 置信区间：0.980-0.995，P = 0.002）。在亲代传播过程中，(TTTCA)exp计数显著增加（P = 0.007），与父代传播相比，母代传播的(TTTCA)exp计数增幅更大（P = 0.013）：结论：(TTTCA)exp 插入是双位点重复扩增中长度依赖性致病成分。结论：(TTTCA)exp 插入物是双位点重复扩增中长度依赖性致病成分，其在亲代传递过程中的不同扩增性质与 FCMTE1 的遗传预期高度相关。© 2024 国际帕金森和运动障碍协会。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.