Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
Centros de Pesquisa Clínica e Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
Clin Genet. 2021 Sep;100(3):258-267. doi: 10.1111/cge.13978. Epub 2021 May 27.
Dominant diseases due to expanded CAG repeat tracts, such as spinocerebellar ataxia type 2 (SCA2), are prone to anticipation and worsening of clinical picture in subsequent generations. There is insufficient data about selective forces acting on the maintenance of these diseases in populations. We made a systematic review and meta-analysis on the effect of the CAG length over age at onset, instability of transmissions, anticipation, de novo or sporadic cases, fitness, segregation of alleles, and ancestral haplotypes. The correlation between CAG expanded and age at onset was r = 0.577, and transmission of the mutant allele was associated with an increase of 2.42 CAG repeats in the next generation and an anticipation of 14.62 years per generation, on average. One de novo and 18 sporadic cases were detected. Affected SCA2 individuals seem to have more children than controls. The expanded allele was less segregated than the 22-repeat allele in children of SCA2 subjects. Several ancestral SCA2 haplotypes were published. Data suggest that SCA2 lineages may tend to disappear eventually, due to strong anticipation phenomena. Whether or not the novel cases come from common haplotypes associated with a predisposition to further expansions is a question that needs to be addressed by future studies.
由于扩展的 CAG 重复序列引起的显性疾病，如脊髓小脑共济失调 2 型（SCA2），容易在后代中出现预期和临床症状恶化。关于这些疾病在人群中维持的选择压力的数据不足。我们对 CAG 长度对发病年龄、传递不稳定性、预期、新发或散发性病例、适应性、等位基因分离和祖先单倍型的影响进行了系统评价和荟萃分析。CAG 扩展与发病年龄之间的相关性为 r = 0.577，突变等位基因的传递与下一代 CAG 重复增加 2.42 个和每代平均预期提前 14.62 年有关。检测到 1 例新发和 18 例散发性病例。受影响的 SCA2 个体似乎比对照组有更多的孩子。在 SCA2 受试者的孩子中，扩展等位基因比 22 重复等位基因的分离程度更低。已经发表了几个 SCA2 的祖先单倍型。数据表明，由于强烈的预期现象，SCA2 谱系最终可能会消失。新病例是否来自与进一步扩展易感性相关的常见单倍型，是一个需要未来研究解决的问题。
