Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.
Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants.
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DOI：
10.1161/circulationaha.109.863076
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发表时间：
2009-11-03
期刊：
影响因子：
37.8
通讯作者：
Ackerman MJ
中科院分区：
文献类型：
--
作者：
Kapa S;Tester DJ;Salisbury BA;Harris-Kerr C;Pungliya MS;Alders M;Wilde AA;Ackerman MJ
长 QT 综合征 (LQTS) 的基因检测具有诊断、预后和治疗意义。 12 个已知的 LQTS 易感基因中的数百个致病突变已被确定。临床上可进行包括 3 种最常见突变基因的基因检测。区分致病突变和无害的罕见变异对于解释测试结果至关重要。我们试图量化突变类型和基因/蛋白质区域在确定突变致病性概率方面的价值。在 388 个不相关的“明确”（临床诊断评分 > 4 和/或 QTc > 480 ms）LQTS 病例和 1300 多个健康对照之间，对每个基因的 KCNQ1 (LQT1)、KCNH2 (LQT2) 和 SCN5A (LQT3) 突变的类型、频率和位置进行了比较。根据这些数据，根据突变类型和位置确定估计预测值（EPV，即在确定病例中发现的导致 LQTS 的突变百分比）。病例中突变的发生率是对照的 10 倍（0.58/病例 vs 0.06/对照）。错义突变是最常见的，在病例中占 KCNQ1、KCNH2 和 SCN5A 突变的 78%、67% 和 89%，在对照中占 >95%。无论位置如何，非错义突变的 EPV >99%。相反，位置似乎对于表征错义突变至关重要。病例和对照之间错义突变的相对频率范围从 SCN5A 域间连接子 (IDL) 中的约 1:1 到 KCNH2 的孔 (P)、跨膜 (TM) 和连接子 (L) 中的无穷大。这些对应的 EPV 范围从 SCN5A IDL 中的 0% 到 KCNH2 TM/L/P 区域中的 100%。 KCNQ1 的 L、P、TM 和 C 末端以及 SCN5A 的 TM/L 的 EPV 也很高。区分致病性突变和罕见变异对于解释 LQTS 基因检测至关重要。突变类型、突变位置和种族特定背景率是预测新突变致病性的关键因素。低 EPV 区域的新突变，例如 SCN5A 的 IDL，应被视为意义不确定的变异 (VUS)，并促使进一步研究以澄清疾病因果关系的可能性。然而，KCNQ1 和 KCNH2 的 TM、L 和 P 等区域的突变可以被自信地定义为高概率导致 LQTS 的突变。这些发现将对涉及突变分析的其他遗传性疾病产生影响。
Genetic testing for long QT syndrome (LQTS) has diagnostic, prognostic, and therapeutic implications. Hundreds of causative mutations in 12 known LQTS-susceptibility genes have been identified. Genetic testing that includes the 3 most commonly mutated genes is available clinically. Distinguishing pathogenic mutations from innocuous rare variants is critical to the interpretation of test results. We sought to quantify the value of mutation type and gene/protein region in determining the probability of pathogenicity for mutations. Type, frequency, and location of mutations across KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A (LQT3) were compared between 388 unrelated “definite” (clinical diagnostic score > 4 and/or QTc > 480 ms) cases of LQTS and over 1300 healthy controls for each gene. From these data, estimated predictive values (EPV, meaning the percent of mutations found in definite cases that would be LQTS-causing) were determined according to mutation type and location. Mutations were 10× more common in cases than controls (0.58/case vs 0.06/control). Missense mutations were the most common, accounting for 78%, 67%, and 89% of mutations in KCNQ1, KCNH2, and SCN5A in cases and >95% in controls. Non-missense mutations have an EPV >99% regardless of location. In contrast, location appears to be critical for characterizing missense mutations. Relative frequency of missense mutations between cases and controls ranged from ~1:1 in the SCN5A interdomain linker (IDL) to infinity in KCNH2’s pore (P), transmembrane (TM), and linker (L). These correspond to EPVs ranging from 0% in the IDL of SCN5A to 100% in the TM/L/P regions of KCNH2. EPV is also high in KCNQ1’s L, P, TM, and C-terminus and the TM/L of SCN5A. Distinguishing pathogenic mutations from rare variants is of critical importance in the interpretation of genetic testing in LQTS. Mutation type, mutation location, and ethnic specific background rates are critical factors in predicting pathogenicity of novel mutations. Novel mutations in low-EPV regions, such as the IDL of SCN5A, should be viewed as variants of uncertain significance (VUS) and prompt further investigation to clarify the likelihood of disease causation. However, mutations in regions such as the TM, L, and P of KCNQ1 and KCNH2 may be defined confidently as high probability LQTS-causing mutations. These findings will have implications for other genetic disorders involving mutational analysis.