Selective forces acting on spinocerebellar ataxia type 3/Machado–Joseph disease recurrency: A systematic review and meta‐analysis,Clinical Genetics

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Selective forces acting on spinocerebellar ataxia type 3/Machado–Joseph disease recurrency: A systematic review and meta‐analysis
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-11-21 , DOI: 10.1111/cge.13888
Lucas Schenatto Sena _{1,

2} , Jordânia Dos Santos Pinheiro _{2,

3} , Maria Luiza Saraiva-Pereira _{1,

2,

4,

5,

6} , Laura Bannach Jardim _{1,

2,

4,

6,

7}

Affiliation

Spinocerebellar ataxia type 3/Machado–Joseph disease (SCA3/MJD) is a dominant neurodegenerative disease caused by the expansion of a CAG repeat tract in ATXN3. Anticipation and worsening of clinical picture in subsequent generations were repeatedly reported, but there is no indication that SCA3/MJD frequency is changing. Thus, we performed a systematic review and meta‐analysis on phenomena with potential effect on SCA3/MJD recurrency in populations: instability of CAG repeat transmissions, anticipation, fitness, and segregation of alleles. Transmission of the mutant allele was associated with an increase of 1.23 CAG repeats in the next generation, and the average change in age at onset showed an anticipation of 7.75 years per generation; but biased recruitments cannot be ruled out. Affected SCA3/MJD individuals had 45% more children than related controls. Transmissions from SCA3/MJD carriers showed that the expanded allele was segregated in 64% of their children. In contrast, transmissions from normal subjects showed that the minor allele was segregated in 54%. The present meta‐analysis concluded that there is a segregation distortion favoring the expanded allele, among children of carriers. Therefore, further studies on transmissions and anticipation phenomena as well as more observations about fertility are required to clarify these selective forces over SCA3/MJD.

中文翻译：

作用于脊髓小脑性共济失调 3 型/马查多-约瑟夫病复发的选择性力量：系统评价和荟萃分析

脊髓小脑性共济失调 3 型/马查多-约瑟夫病 (SCA3/MJD) 是一种显性神经退行性疾病，由ATXN3 中CAG 重复区的扩展引起. 反复报道了后代临床图片的预期和恶化，但没有迹象表明 SCA3/MJD 频率正在发生变化。因此，我们对可能对人群中 SCA3/MJD 复发有潜在影响的现象进行了系统回顾和荟萃分析：CAG 重复传递的不稳定性、预期、适应性和等位基因的分离。突变等位基因的传递与下一代 CAG 重复增加 1.23 次有关，发病年龄的平均变化显示每代预期为 7.75 岁；但不能排除有偏见的招聘。受影响的 SCA3/MJD 个体的孩子比相关对照组多 45%。来自 SCA3/MJD 携带者的传播表明，扩展的等位基因在其 64% 的孩子中分离。相比之下，来自正常受试者的传播表明，次要等位基因被隔离在 54% 中。目前的荟萃分析得出结论，在携带者的孩子中存在有利于扩展等位基因的分离扭曲。因此，需要进一步研究传输和预期现象以及更多关于生育的观察来阐明这些对 SCA3/MJD 的选择力。

更新日期：2020-11-21

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