Despite the advances in high-throughput sequencing, many rare disease patients remain undiagnosed. In particular, the patients with well-defined clinical phenotypes and established clinical diagnosis, yet missing or partial genetic diagnosis, may hold a clue to more complex genetic mechanisms of a disease that could be missed by available clinical tests. Here, we report a patient with a clinical diagnosis of Tuberous sclerosis, combined with unusual secondary features, but negative clinical tests including TSC1 and TSC2 Short-read whole-genome sequencing combined with advanced bioinformatics analyses were successful in uncovering a de novo pericentric 87-Mb inversion with breakpoints in TSC2 and ANKRD11, which explains the TSC clinical diagnosis, and confirms a second underlying monogenic disorder, KBG syndrome. Our findings illustrate how complex variants, such as large inversions, may be missed by clinical tests and further highlight the importance of well-defined clinical diagnoses in uncovering complex molecular mechanisms of a disease, such as complex variants and "double trouble" effects.

中文翻译：

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单一变异，却是“双重麻烦”：由于大的从头倒转而导致 TSC 和 KBG 综合征。

尽管高通量测序取得了进步，但许多罕见疾病患者仍未得到诊断。特别是，具有明确临床表型和已确定的临床诊断但缺失或部分基因诊断的患者可能掌握着疾病更复杂的遗传机制的线索，而现有的临床测试可能会遗漏这些线索。在这里，我们报告一名临床诊断为结节性硬化症的患者，结合不寻常的次要特征，但包括TSC1和TSC2在内的临床测试呈阴性。短读长全基因组测序结合先进的生物信息学分析，成功地发现了从头的中心周 87- TSC2和ANKRD11中存在断点的 Mb 倒置，这解释了 TSC 的临床诊断，并证实了第二种潜在的单基因疾病：KBG 综合征。我们的研究结果说明了临床测试可能会错过复杂的变异（例如大倒位），并进一步强调了明确的临床诊断在揭示疾病的复杂分子机制（例如复杂变异和“双重麻烦”效应）方面的重要性。