台灣馬凡氏症候群之FBN1基因分子診斷與基因型-表現型之分析

馬凡氏症候群是體染色體顯性遺傳疾病，是由於結締組織構造改變使然，影響的系統包含心臟血管、骨骼肌肉以及眼睛，70%的死因為心血管疾病的合併症，最主要的還是主動脈剝離；在院的馬凡氏症患者因剝離的致死率更高達21%；對於馬凡氏症患者首要之務便是減少猝死的可能，利用藥物來預防或延緩主動脈擴大，甚至是在主動脈未剝離前進行預防性的手術；因此確認診斷以及臨床症狀的規則追蹤，越顯重要。基於此目標，於97年4月8日台大醫院正式成立馬凡氏症整合門診，結合台大分子遺傳實驗室發展利用High Resolution Melting檢測FBN1基因的技術，結合門診所收集到的臨床症狀，期待藉此能達到確立診斷以及規則追蹤的目的。自94年3月利用Denaturing High-Performance Liquid Chromatograp hy開始進行FBN1的基因檢測，96年6月以HRM取代DHPLC繼續進行。截至98年1月，四年間共計收案數為157個家族，具有家族史者佔20%(31位個案)，共發現58個突變點位(有兩個不同家族的個案具有相同突變點位)，新發現的突變點位佔72%(42/58)，而檢測率為37%(59/157)。臨床表現的部分，期望能將所有進行基因檢測的個案，將個案的臨床表現加以收集，依照Ghent criteria加以評估，截至98年5月為止，收集具有突變點位個案的phenotype共計56位，wild type共41位，因此，在總收案數中符合Ghent criteria佔32%(50/157)，不符合Ghent criteria佔30%(47/157)，其餘60位個案缺少臨床phenotype的相關資料。近而利用家族史、基因檢測以及Ghent criteria的結果，加以分析比較與統整，更加確認基因檢測、Ghent criteria以及家族史這三項要素，對於馬凡氏症候群的診斷上是非常重要的。因此，依據Ghent criteria進行評估並且加以詢問家族史的部分，加上基因診斷的部分，能更明確地診斷馬凡氏症，亦能更精準地提高檢測率；藉由整合門診的成立，利用基因診斷的技術以及遺傳諮詢的範疇，提供個案更人性化的服務；在genotype-phenotype的聯接研究上，能有更進一步的發現及成果，進而運用在未來的治療，以期建立馬凡氏症候群更完整的資料庫。

關鍵字

馬凡氏症候群；體染色體顯性遺傳；檢測率；家族史

並列摘要

Marfan syndrome is an autosomal dominant inheritance disorder with multisystem connective tissue involvement. The recognized features include cardiovascular, skeletal, and ocular systems; about 70% patients die from cardiovascular complications, and mainly aortic dissection. The in-hospital mortality rate of Marfan patients with dissection is about 21%. Deceasing the possibility of sudden death is the most essential mission for Marfan patients, and using the medicine to prevent/ delay process of the aorta being dilated, even doing the preventive operation before the aorta comes to be dissection. Molecular genetic testing of the FBN1 (Fibrilin-1) gene, the target gene known to be associated with Marfan syndrome, could detect 70 ~ 93% of mutations. Due to the heterogenous clinical manifestations and genetic background, a more sophisticated integration on clinical support including genetic counseling and genetic diagnosis is still warrant. Due to the purpose above, we use high resolution melting (HRM), Automatic sequencing and multiplex ligation-dependent probe amplification (MLPA) to evaluate FBN1 mutations for clinical diagnosing Marfan patients in 2005 ~ 2009. Besides, we set the special clinic to collect the clinical symptom for Marfan patients in National Taiwan University Hospital since 2008. We had screened 157 individual families that 20 % (31/157) cases with family history and identified 58 different mutation (two cases from different family with the same mutation). The detection rate is about 37% (59/157). When family history was taken into consideration, the mutation detection rate rose to 90 % (28/31). We further investigated the phenotypic data and found that 32 % (50/157) cases fit the Ghent criteria for Marfan syndrome, then the detection rate which fitting to criteria rose to 98% (49/50). Therefore, we firmly believe the importance of genetic testing, Ghent criteria and family history to diagnose Marfan syndrome. If we could check every symptom according to Ghent criteria, make the family history much more clear and combine with gene diagnosis, we could not only diagnose Marfan syndrome more explicitly but also enhance the detection ratio more accurately. By combining with the setting of special clinic, genetic diagnosis and comphresive genetic counseling, it is promising that we could provide a better integrated clinical service for Marfan patients, and to have further discovery and achievement in genotype-phenotype correlations to put in use of future treatments and expect to establish greater and more integrated database as well.

並列關鍵字

Marfan syndrome ； Fibrilin-1 ； Ghent criteria ； Detection rate

參考文獻

Ades, L. C., K. J. Holman, et al. (2004). "Ectopia lentis phenotypes and the FBN1 gene." Am J Med Genet A 126A(3): 284-9.

Arbustini, E., M. Grasso, et al. (2005). "Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies." Hum Mutat 26(5): 494

Booms, P., J. Cisler, et al. (1999). "Novel exon skipping mutation in the fibrillin-1 gene: two 'hot spots' for the neonatal Marfan syndrome." Clin Genet 55(2): 110-7.

Collod-Beroud, G. and C. Boileau (2002). "Marfan syndrome in the third Millennium." Eur J Hum Genet 10(11): 673-81.

Dietz, H. C., I. McIntosh, et al. (1993). "Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome." Genomics 17(2): 468-75.

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台灣馬凡氏症候群之FBN1基因分子診斷與基因型-表現型之分析

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