Fujita Atsushi, Suenaga Yuta, Takeshita Eri, Takahashi Yuji, Suzuki Yuichi, Ohori Sachiko, Tsuchida Naomi, Uchiyama Yuri, Koshimizu Eriko, Miyatake Satoko, Mizuguchi Takeshi, Matsumoto Naomichi
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan.
J Hum Genet. 2025 Apr;70(4):227-230. doi: 10.1038/s10038-024-01315-9. Epub 2025 Jan 14.
In monogenic diseases, double mosaic variants of the same gene have rarely been identified. Here, we report the case of triple mosaic variants in PURA, a gene responsible for a neurodevelopmental syndrome (OMIM# 616158). Whole-exome sequencing identified three somatic PURA variants in our case with a similar neurodevelopmental syndrome: NM_005859.5: c.222C>A p.(Tyr74*), c.224T>A p.(Leu75Gln), and c.233A>G p.(Lys78Arg). The two missense variants were on the same sequence read, but the nonsense variant was not. To determine the origin of the alleles, we performed long-read sequencing because of the absence of informative SNPs near the somatic variants. Long-read sequencing revealed that these three somatic variants are derived from the same chromosome. The exact mechanism behind their occurrence is unclear, but the nonsense variant could have occurred de novo as a germline event and incomplete post-zygotic rescue for the germline variant could have led to the two missense variants.
在单基因疾病中，同一基因的双嵌合变异很少被发现。在此，我们报告了一例PURA基因的三嵌合变异病例，该基因与一种神经发育综合征（OMIM# 616158）有关。全外显子测序在我们这个患有类似神经发育综合征的病例中鉴定出三个体细胞PURA变异：NM_005859.5: c.222C>A p.(Tyr74*)、c.224T>A p.(Leu75Gln)和c.233A>G p.(Lys78Arg)。两个错义变异在同一条序列读数上，但无义变异不在。由于体细胞变异附近缺乏信息性单核苷酸多态性（SNP），为了确定等位基因的起源，我们进行了长读长测序。长读长测序显示这三个体细胞变异来自同一条染色体。它们出现背后的确切机制尚不清楚，但无义变异可能作为种系事件从头发生，而对种系变异的不完全合子后挽救可能导致了两个错义变异。
