Genotyping and Genetic Counseling for Patients of the Joint Tuberous Sclerosis Complex Clinics at National Taiwan University Hospital
|Keywords:||結節硬化症;基因檢測;遺傳諮詢;次世代基因序列;Tuberous sclerosis complex (TSC);TS1;TSC2;genetic test;genetic counseling;next-generation sequencing;Sanger sequencing||Issue Date:||2012||Abstract:||
結節硬化症（OMIM 191100）為體染色體顯性遺傳疾病，有極高的穿透率，在腦部、腎臟、肺臟及及其他器官生成缺陷瘤，造成臨床上產生多樣化的症狀，包括癲癇、智能障礙、行為異常及皮膚病變，常造成患者生理與心理上的傷害。結節硬化症患者只有三分之一是遺傳而來，另外三分之二的病人則為新生的突變所致，新生兒發生率為1/6000-1/10000，男女比率相等。目前已知有TSC1(9q34)以及TSC2 (16p13)二個基因突變造成，可確認的突變在結節硬化症約70-80%左右。
本研究於「臺大醫院結節硬化症整合門診」的病友所提供的血液，利用次世代定序分析(Illumina system)針對47位已確診為結節硬化症及6位可能是結節硬化症的個案，進行TSC1及TSC2基因突變點位檢測。其結果共檢出35位TSC1或TSC2基因序列異常且會影響基因功能的變異位置。然後再從篩檢出可能具有臨床意義之變異的35位TSC患者及其家屬81位，進行聚合酶連鎖反應及標準Sanger sequencing方法做DNA定序進行檢測。其中有16位個案以前做過基因檢測報告，亦列為比對參考。研究期間，共做七例遺傳諮詢紀錄。
Tuberous sclerosis complex (TSC[OMIM 191100])is an autosomal dominant disease with high penetrance, characterized by the presence of hamartomas in brain, kidneys, lungs and/or other multiple organ systems. The clinical manifestations include epilepsy, mental retardation, behavioral problems, skin lesions, renal problems, which often cause harm to patients physically and psychologically. Two thirds of patients are sporadic and are thought to represent de novo mutation. Approximately one in 6,000 to one in 10,000 newborns are affected by TSC. Males and females are equally susceptible to have TSC and the chance of passing it on to offspring is 50%. TSC is caused by inactivating genetic variant at either TSC1(9q34) or TSC2 (16p13) gene. About 70% to 80% of individuals who meet definite diagnostic criteria have a small identifiable TSC1 or TSC2 gene causative variant.
Genetic testing for TSC patients has many important implications, including, but not limited to, confirmation of the diagnosis, identification of the causative variants of the patient/pedigree, and genetic counseling. The results of genetic testing may be helpful for patients, family members, medical professionals and policymakers. However, there are a total of 64 exons in TSC1 and TSC2 genes, which causative variants genetic testing for TSC to be time-consuming and expensive. It is not uncommon that genetic testing is delayed because the family cannot afford the cost.
The Joint TSC Clinics at National Taiwan University Hospital was established in July 2010. A TSC patient can get access to almost all medical professionals related to his/her medical needs at a single visit, which greatly facilitate holistic health care and multi-disciplinary collaboration. The Clinics is a one-stop solution, and provide comprehensive health care for TSC patients.
The study was approved by the Institutional Review Board (IRB) of National Taiwan University Hospital. After obtaining informed consent, we collected blood samples from 47 definite and 6 possible TSC patients and their family members at the Joint Tuberous Sclerosis Complex Clinics at National Taiwan University Hospital. We performed genotyping using next-generation sequencing (NGS) (Illumina system) technology for detecting genetic variants at the TSC1 and TSC2 genes. For possible causative variants detected in the NGS experiment, we further verified the results using traditional Sanger sequencing. Sixteen patients were previously genotyped by traditional methods; we therefore made a quick comparison between the genotyping results between the new NGS method and the traditional methods. We also performed genetic counseling for 7 families during the study period.
Among the 47 patients with definite TSC diagnosis, we could identify the causative genetic variants for 34 patients (72%), a detection rate comparable with the traditional method. Among the 16 patients previously genotyped, all the results were the same, except for two patients that we identified the causative variants which had been missed using the traditional way. We found NGS to have several advantages as a genotyping tools for TSC diagnosis, including high accuracy, high speed and relatively low cost. In the future, NGS may prove to be a valuable tool for TSC genetic diagnosis. Professional genetic counseling services will also help TSC patients and families through risk prediction and disease understanding. We hope that our comprehensive TSC care system, including the genetic testing modality and genetic counseling, can help early diagnosis and multi-disciplinary treatment of TSC patients, and reduce the number of new TSC patients from known families. The insights gained from genetic study and molecular mechanism might further facilitate the progress of medical research and provide better choices for TSC treatment.
|Appears in Collections:||分子醫學研究所|
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