Detection of gonosomal mosaicism by ultra‐deep sequencing and droplet digital PCR in patients with Emery–Dreifuss muscular dystrophy

Abstract

Background 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. Methods 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. Results 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. Conclusion 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.