Case Report: Low-Level Maternal Mosaicism of a Novel CREBBP Variant Causes Recurrent Rubinstein-Taybi Syndrome in Two Siblings of a Chinese Family.
Case Report: Low-Level Maternal Mosaicism of a Novel CREBBP Variant Causes Recurrent Rubinstein-Taybi Syndrome in Two Siblings of a Chinese Family.
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病例报告：新型 CREBBP 变异体的低水平母体嵌合导致中国家庭的两个兄弟姐妹复发鲁宾斯坦-泰比综合征
DOI：
10.3389/fgene.2021.640992
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发表时间：
2021
影响因子：
3.7
通讯作者：
Luo Y
中科院分区：
文献类型：
--
作者：
Lin S;He Z;Huang L;Liu J;Lei T;Wu J;Huang P;Zhou Y;Luo Y
家族性 Rubinstein-Taybi 综合征 (RSTS) 的兄弟姐妹和明显未受影响的父母患有复发性 RSTS 的情况很少见；这种情况可能是由父母的体细胞和/或种系嵌合引起的。 CREBBP 相关 RSTS 家族中亲本低水平（<10%）种系嵌合尚未见报道。在这里，我们展示了对一个中国家庭的研究，该家庭有两个 RSTS 兄弟姐妹和显然未受影响的父母。我们通过三重全外显子组测序在兄弟姐妹的 CREBBP 中检测到明显的从头变异 (DNV) c.3235C>T (p.Gln1079*)。对父母进行的高深度下一代测序（NGS）显示，未受影响母亲的外周血（3.64％）和颊粘膜（1.94％）中存在低水平（<10％）嵌合变异，表明母体体细胞和种系嵌合。对患者和正常个体的外周血 RNA 测序分析表明，c.3235C>T (p.Gln1079*) 无义变异不会触发无义介导的 mRNA 衰减，从而降低 CREBBP mRNA 水平。转录组分析显示，患者和正常个体之间有 151 个 mRNA 下调和 132 个 mRNA 上调。这项研究强调，使用多个样本的高深度 NGS 可能适用于有明显 CREBBP DNV 引起的兄弟姐妹受影响的家庭，以识别潜在的低水平父母嵌合体并提供复发风险评估。
Familial Rubinstein-Taybi syndrome (RSTS) with recurrent RSTS siblings and apparently unaffected parents is rare; such cases might result from parental somatic and/or germline mosaicism. Parental low-level (<10%) germline mosaicism in the CREBBP-associated RSTS family has not been reported. Here, we present our studies of a Chinese family with two RSTS siblings and apparently unaffected parents. We detected the apparent de novo variant (DNV) c.3235C>T (p.Gln1079*) in CREBBP in the siblings via trio whole-exome sequencing. High-depth next-generation sequencing (NGS) for the parents revealed a low-level (<10%) mosaic variant in both the peripheral blood (3.64%) and buccal mucosa (1.94%) of the unaffected mother, indicating maternal somatic and germline mosaicism. Peripheral blood RNA-sequencing analysis for the patients and normal individuals indicated that the c.3235C>T (p.Gln1079*) non-sense variant did not trigger nonsense-mediated mRNA decay to reduce CREBBP mRNA levels. Transcriptome analysis revealed 151 downregulated mRNAs and 132 upregulated mRNAs between the patients and normal individuals. This study emphasizes that high-depth NGS using multiple specimens might be applied for a family with an affected sibling caused by an apparent CREBBP DNV to identify potential low-level parental mosaicism and provide an assessment of recurrence risk.