Department of Neurology, Maastricht University Medical Center+, Maastricht, The Netherlands.
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands.
Eur J Hum Genet. 2020 Jul;28(7):956-962. doi: 10.1038/s41431-020-0601-4. Epub 2020 Mar 12.
Myotonic dystrophy type 1 (DM1) is caused by a CTG trinucleotide repeat expansion on chromosome 19q13.3. While DM1 premutation (36-50 repeats) and protomutation (51-80 repeats) allele carriers are mostly asymptomatic, offspring is at risk of inheriting expanded, symptom-associated, (CTG)n repeats of n > 80. In this study we aimed to evaluate the intergenerational instability of DM1 pre- and protomutation alleles, focussing on the influence of parental gender. One hundred and forty-six parent-child pairs (34 parental premutations, 112 protomutations) were retrospectively selected from the DM1 patient cohort of the Maastricht University Medical Center+. CTG repeat size of parents and children was determined by (triplet-primed) PCR followed by fragment length analysis and Southern blot analysis. Fifty-eight out of eighty-one (71.6%) paternal transmissions led to a (CTG)n repeat of n > 80 in offspring, compared with 15 out of 65 (23.1%) maternal transmissions (p < 0.001). Repeat length instability occurred for paternal (CTG)n repeats of n ≥ 45, while maternal instability did not occur until (CTG)n repeats reached a length of n ≥ 71. Transmission of premutations caused (CTG)n repeats of n > 80 in offspring only when paternally transmitted (two cases), while protomutations caused (CTG)n repeats of n > 80 in offspring in 71 cases, of which 56 (78.9%) were paternally transmitted. In conclusion, our data show that paternally transmitted pre- and protomutations were more unstable than maternally transmitted pre- and protomutations. For genetic counseling, this implies that males with a small DMPK mutation have a higher risk of symptomatic offspring compared with females. Consequently, we suggest addressing sex-dependent factors in genetic counseling of small-sized CTG repeat carriers.
1 型肌强直性营养不良（DM1）是由 19q13.3 染色体上的 CTG 三核苷酸重复扩展引起的。虽然 DM1 前突变（36-50 个重复）和原突变（51-80 个重复）等位基因携带者大多无症状，但后代有继承扩展的、与症状相关的（CTG）n 重复的风险，n > 80。在这项研究中，我们旨在评估 DM1 前突变和原突变等位基因的代际不稳定性，重点关注父母性别对其的影响。从马斯特里赫特大学医学中心+的 DM1 患者队列中回顾性选择了 146 对父母-子女对（34 对父母前突变，112 对原突变）。通过（三联体引物）PCR 后片段长度分析和 Southern blot 分析确定父母和子女的 CTG 重复大小。在 81 个（71.6%）父系传递中，后代的（CTG）n 重复长度 n > 80，而在 65 个（23.1%）母系传递中，后代的（CTG）n 重复长度 n > 80（p < 0.001）。父系（CTG）n 重复长度 n ≥ 45 时会发生重复长度不稳定性，而母系不稳定性只有在（CTG）n 重复长度达到 n ≥ 71 时才会发生。前突变的传递仅在父系传递时导致后代的（CTG）n 重复长度 n > 80（两例），而原突变的传递在 71 例中导致后代的（CTG）n 重复长度 n > 80，其中 56 例（78.9%）为父系传递。总之，我们的数据表明，父系传递的前突变和原突变比母系传递的前突变和原突变更不稳定。对于遗传咨询，这意味着携带较小 DMPK 突变的男性与女性相比，其有症状后代的风险更高。因此，我们建议在遗传咨询小型 CTG 重复携带者时考虑性别相关因素。
