PURPOSE To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders. METHODS We recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified. RESULTS Pathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers. CONCLUSION This is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.

中文翻译：

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Rett综合征队列的发病机制和遗传中的基因组嵌合体。

目的 确定嵌合体在 Rett 和 Rett 样疾病的发病机制和遗传中的作用。方法 我们招募了 471 名 Rett 和 Rett 样患者。进行了针对 MECP2、CDKL5 和 FOXG1 的面板测序。通过贝叶斯基因分型器对 147 名患者的镶嵌现象进行了量化。候选者通过扩增子测序和数字 PCR 进行验证。对携带致病性 MECP2 变异的 21 名父亲的种系嵌合体进行了进一步量化。结果 在 324/471 (68.7%) 名患者中发现了 MECP2/CDKL5/FOXG1 的致病变异。体细胞 MECP2 嵌合体在 5/471 (1.1%) 患者中得到证实，包括 3/18 男性 (16.7%) 和 2/453 女性 (0.4%)。5 名体细胞 MECP2 嵌合体患者中有 3 人在 MECP2-Arg106 存在嵌合体。在 5/21 (23.8%) 的父亲中检测到生殖系 MECP2 嵌合体。结论 这是在队列水平上首次系统筛选体细胞和父系生殖系 MECP2 嵌合体。我们的研究结果表明，体细胞 MECP2 嵌合直接导致 Rett 综合征的致病性，尤其是在男性患者中。MECP2-Arg106 可能是一个镶嵌热点。父系种系 MECP2 嵌合的高比例表明 MECP2 变体的父系起源偏倚的机制被低估了。最后，这项研究为未来研究由强父系起源的从头变异引起的遗传疾病提供了经验基础。MECP2-Arg106 可能是一个镶嵌热点。父系种系 MECP2 嵌合的高比例表明 MECP2 变体的父系起源偏倚的机制被低估了。最后，这项研究为未来研究由强父系起源的从头变异引起的遗传疾病提供了经验基础。MECP2-Arg106 可能是一个镶嵌热点。父系种系 MECP2 嵌合的高比例表明 MECP2 变体的父系起源偏倚的机制被低估了。最后，这项研究为未来研究由强父系起源的从头变异引起的遗传疾病提供了经验基础。