First report of ATP2A2 somatic mosaicism occurring during embryogenesis in transient acantholytic dermatosis

• Published in: JEADV clinical practice 2024-09, Vol.3 (4), p.1227-1230
• Main Authors: Hiromatsu, Emi, Abe, Toshifumi, Teye, Kwesi, Koga, Hiroshi, Ishii, Norito, Hamada, Takahiro, Nakama, Takekuni
• Format: Article
• Language: English
• Subjects: Darier disease; ddPCR; intracellular Ca2; mutant allelic fraction
• ISSN: 2768-6566; 2768-6566
• DOI: 10.1002/jvc2.371

Transient acantholytic dermatosis (TAD) is a relatively common skin disease that typically affects older individuals, which shows clinical and histologic similarities to autosomal dominant Darier disease. TAD was recently shown to be caused by somatic ATP2A2 damaging variants. In this study, we performed Sanger sequencing and droplet digital PCR (ddPCR) in a Japanese elderly male with TAD to identify ATP2A2 somatic mosaicism occurring during embryogenesis for the first time and mutant allelic fraction (MAF). Sanger sequencing revealed a known heterozygous substitution c.1645C>T, p.Arg549* in ATP2A2 from blood and the affected skin containing the epidermis and dermis, whereas the signals of the mutated allele were weaker, suggesting that discrepancy of signal intensities demonstrates the presence of somatic mosaicism. By ddPCR, the normal and mutant allele were identified in genomic DNAs and the MAFs were 20.1% (affected skin) and 14.7% (blood), respectively. In the present case, somatic mosaicisms observed in ectodermal (epidermis) and mesodermal (dermis and blood) origin DNA can be explained by a mutational event during the early‐stage differentiation of embryonic epiblast in embryogenesis, and mutant embryonic cells somewhat preferentially differentiate to form the epidermis, rather than the dermis and blood. Disrupted intracellular Ca2+ homoeostasis through clinical deterioration together with ATP2A2 somatic mosaicism in this patient might result in transient skin eruptions. Transient acantholytic dermatosis (TAD) is a common skin disease showing clinical and histologic similarities to Darier disease. In this study, we have identified for the first time ATP2A2 somatic mosaicism (c.1645C>T, p.Arg549*) occurring during embryogenesis in a Japanese patient with TAD. By droplet digital PCR, the mutant allelic fractions were 20.1% in affected skin and 14.7% in blood. Disrupted intracellular Ca2+ homoeostasis through clinical deterioration together with ATP2A2 somatic mosaicism in this patient might result in transient skin eruptions.