Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
Genetic and Metabolic Central Laboratory, Guangxi Birth Defects Research and Prevention Institute, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
Mol Genet Genomic Med. 2023 Jun;11(6):e2161. doi: 10.1002/mgg3.2161. Epub 2023 Mar 10.
Emery-Dreifuss muscular dystrophy (EDMD2) is a rare form of muscular dystrophy that is inherited as an autosomal dominant trait. In some patients, it is inherited from parental mosaicism, and this increases the recurrence risk significantly. The presence of mosaicism is underestimated due to the limitations of genetic testing and the difficulty in obtaining samples.
A peripheral blood sample from a 9-year-old girl with EDMD2 was analyzed by enhanced whole exome sequencing (WES). Sanger sequencing in her unaffected parents and younger sister was performed for validation. In the mother, ultra-deep sequencing and droplet digital PCR (ddPCR) in multiple samples (blood, urine, saliva, oral epithelium, and nail clippings) were performed in order to identify the suspected mosaicism of the variant.
WES revealed a heterozygous mutation (LMNA, c.1622G>A) in the proband. Sanger sequencing of the mother suggested the presence of mosaicism. The ratio of mosaic mutation was confirmed in different samples by ultra-deep sequencing and ddPCR (19.98%-28.61% and 17.94%-28.33%, respectively). This inferred that the mosaic mutation may have occurred early during embryonic development and that the mother had gonosomal mosaicism.
We described a case of EDMD2 caused by maternal gonosomal mosaicism which was confirmed by using ultra-deep sequencing and ddPCR. This study illustrates the importance of a systematic and comprehensive screening of parental mosaicism with more sensitive approaches and the use of multiple tissue samples.
先天性肌营养不良症 2 型（EDMD2）是一种罕见的肌营养不良症，呈常染色体显性遗传。在一些患者中，它是从父母的嵌合体遗传而来，这显著增加了复发风险。由于遗传检测的局限性和获取样本的困难，嵌合体的存在被低估了。
对一名 9 岁患有 EDMD2 的女孩的外周血样本进行了增强全外显子组测序（WES）分析。对其未受影响的父母和妹妹进行了 Sanger 测序验证。在母亲中，对多个样本（血液、尿液、唾液、口腔上皮和指甲屑）进行了超深度测序和数字液滴 PCR（ddPCR），以鉴定该变异的疑似嵌合体。
WES 显示先证者存在杂合突变（LMNA，c.1622G>A）。母亲的 Sanger 测序提示存在嵌合体。超深度测序和 ddPCR 分别在不同样本中确认了嵌合突变的比例（19.98%-28.61%和 17.94%-28.33%）。这表明嵌合突变可能发生在胚胎发育早期，母亲存在性染色体嵌合体。
我们描述了一例由母亲性染色体嵌合体引起的 EDMD2 病例，该病例通过超深度测序和 ddPCR 得到了证实。本研究说明了采用更敏感的方法和多个组织样本对父母嵌合体进行系统全面筛查的重要性。
