Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by non-cancerous tumors in multiple organs including the brain, kidney, lung, heart, and skin. We encountered a Japanese family consisting of two siblings (a four-year-old boy and a one-year-old girl) with multiple cardiac rhabdomyomas conveying a high risk of TSC and apparently unaffected sibling (a two-year-old girl) and parents. Whole exome sequencing and application of Integrative Genomic Viewer revealed an identical intragenic TSC1 deletion with the breakpoints on intron 15 and exon 19 in the affected siblings, but not in the apparently unaffected sibling and parents. Subsequently, PCR-based analyses were performed using primers flanking the deletion, showing that the deletion was also present in the father and that the deletion occurred between chr9:135,777,038 (bp) and chr9:135,780,540 (bp) in association with a one bp overlap. Furthermore, RT-PCR analyses were carried out using lymphoblastoid cell lines, revealing a major in-frame insertion/deletion transcript produced by aberrant splicing using a cryptic ″ag″ splice acceptor motif at intron 15 (r.1998_2438delinsTTCATTAGGTGG) and a minor frameshift transcript generated by aberrant splicing between exon 15 and exon 20 (r.1998_2502del, p.Lys666Asnfs*15) in the affected siblings. These findings imply that the intragenic deletion producing two aberrant transcripts was generated as a somatic pathogenic variant involving the germline in the father and was transmitted to the affected siblings.

结节性硬化症（TSC）是一种罕见的常染色体显性遗传疾病，其特征在于多个器官（包括脑，肾，肺，心脏和皮肤）的非癌性肿瘤。我们遇到了一个日本家庭，该家庭由两个兄弟姐妹（一个四岁男孩和一个一岁女孩）组成，多发性横纹肌瘤易患TSC，显然兄弟姐妹（一个两岁女孩）未受影响。父母。完整的外显子组测序和Integrative Genomic Viewer的应用揭示了相同的基因内TSC1在受影响的兄弟姐妹中使用内含子15和外显子19的断点进行删除，但在未受影响的兄弟姐妹和父母中则没有。随后，使用缺失侧翼的引物进行了基于PCR的分析，表明该缺失也存在于父亲中，并且该缺失发生在chr9：135,777,038（bp）和chr9：135,780,540（bp）之间，且重叠了一个bp。 。此外，使用淋巴母细胞样细胞系进行了RT-PCR分析，揭示了一个主要的框内插入/缺失转录本，是通过在内含子15（r.1998_2438delinsTTCATTAGGTGG）上使用隐含的“ ag”剪接受体基序进行异常剪接产生的。通过在受影响的同胞中外显子15和外显子20（r.1998_2502del，p.Lys666Asnfs * 15）之间进行异常剪接产生。