Low penetrance in the long-QT syndrome - Clinical impact
Low penetrance in the long-QT syndrome - Clinical impact
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DOI：
10.1161/01.cir.99.4.529
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发表时间：
1999-02-02
期刊：
影响因子：
37.8
通讯作者：
Schwartz, PJ
中科院分区：
文献类型：
--
作者：
Priori, SG;Napolitano, C;Schwartz, PJ
背景-目前仍然认为大多数受长QT综合征（LQTS）影响的患者表现出QT间期延长或临床症状。这反映在连锁研究中的假设，即90%的连锁率。我们以前曾建议，一个大于预期的LQTS患者的数量可能会受到影响，而不显示临床症状，我们现在已经利用分子诊断的可用性来测试这一hypothesis.Methods和Results-We确定了9个家庭的“散发”的情况下，LOTS，即家庭中，除了先证者，没有家庭成员的临床症状的疾病。对先证者和家庭成员的DNA进行常规单链构象多态性和测序的突变筛查，以识别突变携带者。在46名临床上认为未受影响的家庭成员中，15名（33%）被发现是基因携带者，外显率为25%。在这些家庭中，传统的临床诊断标准的灵敏度只有38%，在正确识别载体的遗传缺陷。结论-这项研究表明，在某些家庭中，LQTS可能会出现一个非常低的randrance，发现与多个临床意义。被认为是正常的家庭成员，发现是沉默基因携带者，如果暴露于阻断钾通道的心脏或非心脏药物，意外地有产生受影响后代的风险，也有发生尖端扭转型室性心动过速的风险。纯粹基于临床理由，排除确定受影响患者家属中的LOTS已不再被接受。相反，现在似乎适合在基因分型患者的所有家庭成员中进行分子筛查。
Background-It is still currently held that most patients affected by the long-QT syndrome (LQTS) show QT interval prolongation or clinical symptoms. This is reflected by the assumption in linkage studies of a penetrance of 90%. We had previously suggested that a larger-than-anticipated number of LQTS patients might be affected without showing clinical signs, We have now exploited the availability of molecular diagnosis to test this hypothesis.Methods and Results-We identified 9 families with "sporadic" cases of LOTS, ie, families in which, besides the proband, none of the family members had clinical signs of the disease. Mutation screening by conventional single-strand conformational polymorphism and sequencing was performed on DNA of probands and family members to identify mutation carriers. Of 46 family members considered on clinical grounds to be nonaffected, 15 (33%) were found instead to be gene carriers, Penetrance was found to be 25%. In these families, conventional clinical diagnostic criteria had a sensitivity of only 38% in correctly identifying carriers of the genetic defect.Conclusions-This study demonstrates that in some families, LQTS may appear with a very low penetrance, a finding with multiple clinical implications. The family members considered to be normal and found to be silent gene carriers are unexpectedly at risk of generating affected offspring and also of developing torsade de pointes if exposed to either cardiac or noncardiac drugs that block potassium channels. It is no longer acceptable to exclude LOTS among family members of definitely affected patients on purely clinical grounds. Conversely, it now appears appropriate to perform molecular screening in all family members of genotyped patients.