In myotonic dystrophy type 1 (DM1), somatic mosaicism of the (CTG)_n repeat expansion is age-dependent, tissue-specific and expansion-biased. These features contribute toward variation in disease severity and confound genotype-to-phenotype analyses. To investigate how the (CTG)_n repeat expansion changes over time, we collected three longitudinal blood DNA samples separated by 8–15 years and used small pool and single-molecule PCR in 43 DM1 patients. We used the lower boundary of the allele length distribution as the best estimate for the inherited progenitor allele length (ePAL), which is itself the best predictor of disease severity. Although in most patients the lower boundary of the allele length distribution was conserved over time, in many this estimate also increased with age, suggesting samples for research studies and clinical trials should be obtained as early as possible. As expected, the modal allele length increased over time, driven primarily by ePAL, age-at-sampling and the time interval. As expected, small expansions <100 repeats did not expand as rapidly as larger alleles. However, the rate of expansion of very large alleles was not obviously proportionally higher. This may, at least in part, be a result of the allele length-dependent increase in large contractions that we also observed. We also determined that individual-specific variation in the increase of modal allele length over time not accounted for by ePAL, age-at-sampling and time was inversely associated with individual-specific variation in age-at-onset not accounted for by ePAL, further highlighting somatic expansion as a therapeutic target in DM1.

中文翻译：

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肌强直性营养不良 1 型中扩展的 CTG 重复序列的体细胞嵌合体的纵向增加与发病年龄的变化有关。

在肌强直性营养不良 1 型 (DM1) 中，(CTG) _n重复扩增的体细胞嵌合现象与年龄相关、组织特异性和扩增偏向性。这些特征导致疾病严重程度的变化和混淆基因型到表型分析。调查 (CTG) _n重复扩增随时间的变化，我们收集了相隔 8-15 年的三个纵向血液 DNA 样本，并在 43 名 DM1 患者中使用了小池和单分子 PCR。我们使用等位基因长度分布的下限作为遗传祖细胞等位基因长度 (ePAL) 的最佳估计值，ePAL 本身就是疾病严重程度的最佳预测指标。尽管在大多数患者中，等位基因长度分布的下限随着时间的推移而保持不变，但在许多情况下，这一估计值也随着年龄的增长而增加，这表明应尽早获取用于研究和临床试验的样本。正如预期的那样，模态等位基因长度随时间增加，主要由 ePAL、采样年龄和时间间隔驱动。正如预期的那样，<100 次重复的小扩增没有像较大的等位基因那样迅速扩增。然而，非常大的等位基因的扩增率并不明显成比例地更高。这可能至少部分是我们也观察到的大收缩的等位基因长度依赖性增加的结果。我们还确定，ePAL 无法解释的模态等位基因长度随时间增加的个体特异性变异、采样年龄和时间与 ePAL 未解释的个体特异性发病年龄变异呈负相关，进一步强调体细胞扩张作为 DM1 的治疗靶点。