Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura, Kanazawa-ku, Japan.
Clin Genet. 2011 Nov;80(5):484-8. doi: 10.1111/j.1399-0004.2010.01575.x. Epub 2010 Nov 10.
Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. We have recently identified that the de novo mutations of STXBP1 are important causes for OS. Here we report a paternal somatic mosaicism of an STXBP1 mutation. The affected daughter had onset of spasms at 1 month of age, and interictal electroencephalogram showed suppression-burst pattern, leading to the diagnosis of OS. She had a heterozygous c.902+5G>A mutation of STXBP1, which affects donor splicing of exon 10, resulting in 138-bp insertion of intron 10 sequences in the transcript. The mutant transcript had a premature stop codon, and was degraded by nonsense-mediated mRNA decay in lymphoblastoid cells derived from the patient. High-resolution melting analysis of clinically unaffected parental DNAs suggested that the father was somatic mosaic for the mutation, which was also suggested by sequencing. Cloning of PCR products amplified with the paternal DNA samples extracted from blood, saliva, buccal cells, and nails suggested that 5.3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS.
大田原综合征（OS）是最严重和最早出现的癫痫形式之一。我们最近发现 STXBP1 的新生突变是 OS 的重要原因。在这里，我们报告了 STXBP1 突变的父源体细嵌合现象。受影响的女儿在 1 个月大时出现痉挛发作，发作间期脑电图显示抑制-爆发模式，导致 OS 的诊断。她携带 STXBP1 的杂合 c.902+5G>A 突变，影响外显子 10 的供体位点剪接，导致转录本中 10 号内含子序列插入 138 个碱基对。突变转录本含有一个提前终止密码子，并在源自患者的淋巴母细胞中通过无意义介导的 mRNA 衰变而降解。对临床未受影响的父母 DNA 进行高分辨率熔解分析表明，父亲是该突变的体细嵌合体，测序也证实了这一点。从父亲的血液、唾液、口腔细胞和指甲中提取的 DNA 样本进行 PCR 产物克隆表明，分别有 5.3%、8.7%、11.9%和 16.9%的等位基因携带该突变。这是 STXBP1 突变体细嵌合现象的首次报告，对 OS 的遗传咨询具有重要意义。
