Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica.
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Hum Mol Genet. 2020 Aug 29;29(15):2496-2507. doi: 10.1093/hmg/ddaa123.
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.
在 1 型肌强直性营养不良（DM1）中，（CTG）n 重复扩展的体嵌合现象具有年龄依赖性、组织特异性和扩展偏倚性。这些特征导致疾病严重程度的差异，并混淆了基因型与表型分析。为了研究（CTG）n 重复扩展如何随时间变化，我们收集了 43 名 DM1 患者相隔 8-15 年的三个纵向血液 DNA 样本，并使用小池和单分子 PCR 进行分析。我们使用等位基因长度分布的下限作为遗传前体等位基因长度（ePAL）的最佳估计值，ePAL 本身是疾病严重程度的最佳预测因子。尽管在大多数患者中，等位基因长度分布的下限随时间保持不变，但在许多患者中，该估计值也随年龄增加，这表明研究和临床试验的样本应尽早获得。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 个重复的小扩展没有像较大等位基因那样迅速扩展。然而，非常大的等位基因的扩展速度并没有明显更高。这至少部分是由于我们也观察到的与等位基因长度相关的大收缩增加。我们还确定，模态等位基因长度随时间增加的个体间差异，不能用 ePAL、采样年龄和时间来解释，与不能用 ePAL 解释的发病年龄的个体间差异呈负相关，进一步强调了作为 DM1 治疗靶点的体细胞扩展。
