Department of Dermatology, Keio University School of Medicine, Tokyo, Japan.
Department of Maternal-Fetal Biology, National Center for Child Health and Development, Tokyo, Japan.
Eur J Hum Genet. 2023 Jun;31(6):716-720. doi: 10.1038/s41431-023-01316-w. Epub 2023 Mar 15.
A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.
胚胎中携带先天性致病变异等位基因的野生型等位基因发生产前二次遗传变化，导致基因的单等位基因和双等位基因缺陷镶嵌现象，这种现象被称为叠加镶嵌现象。Hailey-Hailey 病（HHD）的叠加镶嵌现象已在一个家族病例中得到证实。在这里，我们报告了两例无关的 HHD 叠加镶嵌病例：ATP2C1 的先天性单等位基因致病性变异，随后是合子后拷贝中性杂合性丢失。独特的是，在就诊时，两名患者均没有 HHD 的家族史。在第一个病例中，先天性致病性变异是新生的。在第二个病例中，父亲携带致病性变异，但尚未出现皮肤症状。我们的病例表明，HHD 中的叠加镶嵌现象可能没有家族史，遗传分析对于分类镶嵌类型和评估家族发生风险至关重要。
