| Summary: | 碩士 === 國立臺灣大學 === 分子醫學研究所 === 107 === Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by pathogenic variants of the TSC1 or TSC2 genes, which could result in hamartomas or abnormal hyperplasia in multiple organs. It shows autosomal dominant inheritance. Considering the widespread manifestations in TSC patients, medical care for the patients becomes quite challenging. Therefore, this study aimed to provide genetic diagnosis taking advantage of next-generation sequencing (NGS), and also integrated clinical care.
Through the Integrated TSC Clinic of National Taiwan University Hospital, we recruited 532 subjects in 239 families into this project. After thorough evaluations based on the diagnostic crietria of TSC, 180 among the 239 probands were confirmed to be TSC patients, 10 were suspicious TSC cases, and 49 individuals were excluded as TSC patients. With the informed consents from the participants, we collected, registered, recorded, and consolidated their clinical data into the Integrated Database of Tuberous Sclerosis Complex, using a REDCap (Research Electronic Data Capture) system. For the suspected TSC patients, NGS could sometimes provide critical information for the correct diagnosis. For several patients showing unstable blood everolimus concentration, we performed a pharmacogenomics study (including the CYP3A4 and ABCB1 genes). For a TSC family carrying multiple cancers in multiple individuals, we conducted whole genome sequencing (WGS) of 4 individuals, attempting to identify the cancer-causing gene(s). We also investigated the clinical course of renal angiomyolipoma in women during pregnancy and after delivery.
Of all the TSC probands receiving our NGS-based genetic testing, 89% were found to have pathogenic or likely pathogenic variants in TSC1 or TSC2, 3% with variation of unknown significance (VUS), and 8% were negative. Among the diagnosed patients, 21% of them were caused by TSC1 while the rest 79% were caused by TSC2. The disease-causing variants were inherited in 30% of probands, and were de novo mutations in 70% of the probands. According to the aforementioned statistics, this research has confirmed that the current epidemiological condition of TSC in Taiwan does not have a significant difference compared to the ratios presented in previous literature.
For integrated clinic care, we investigated several aspects. First, we performed pharmacogenomic testing related to the mTOR inhibitor, everolimus, focusing on genetic variations of CYP3A4 and ABCB1 genes. Currently, there were 64 patients involved in this study with the permission to collect personal information, therapeutic drug monitoring, medicine dosage, other medication, symptom changes, and related data for evaluating the therapeutic effect and medication-use safety of the subjects. Second, for a TSC family with early-onsent and multiple primary cancers, we performed WGS in 4 individuals. After thorough analysis, we identified a splicing variation of the TRIM45 gene, which co-segregated in affected individuals. From the literature review, a handful of studies suggested that TRIM45 gene might possess a function of tumor suppressor; however, the data were not conclusive. We will continue working on the issue to clarify if TRIM45 indeed is the causing gene of those cancers in this family. This work might help to confirm TRIM45 as a genuine novel tumor suppressor gene. Third, this study presented a case series of female renal angiomyolipoma patients before, during, and after pregnancy. Through the observation, we hoped to develop an in-depth discussion about the healthcare and genetic counseling in female renal angiomyolipoma patients with TSC.
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