Evidence of genetic heterogeneity in the long QT syndrome.
Evidence of genetic heterogeneity in the long QT syndrome.
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长 QT 综合征遗传异质性的证据。
DOI：
10.1126/science.8316839
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发表时间：
1993
期刊：
影响因子：
--
通讯作者：
Kerem,BS
中科院分区：
文献类型：
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作者：
Benhorin,J;Kalman,YM;Medina,A;Towbin,J;Rave-Harel,N;Dyer,TD;Blangero,J;MacCluer,JW;Kerem,BS
0图2. H-ras-1与LOT连锁的特征lod函数。底部曲线显示来自组合连锁和分离分析的lod分数（0= 0.494）。顶部曲线显示来自常规连锁分析的lod分数（δ = 0.500）。完全显性等位基因（7）。我们使用这个主要的基因座和H-ras-1标记在一个联合的连锁和分离分析。该分析（图2，底部曲线）表明，在我们的研究中，主要的LQT基因座与H-ras-1并不紧密连锁。重组分数的最佳估计值为0.494，接近于0。第50章没有联系连锁可通过常规排除标准（lod评分为-2.0，其对应于P值为0.0024）在< 0.13时排除，或通过卡方检验（P= 0.05）在0< 0.23时排除。第二，与Keating等人的结果进行比较。(3)我们使用他们的假设（显性疾病等位基因的频率为0.001和0.9个等位基因）和他们的表型定义进行了传统的连锁分析。他们的表型定义与我们使用的定义略有不同（表1），导致我们研究的谱系中18个个体的状态发生变化，其中17个从未受影响到模棱两可，1个从受影响到模棱两可。根据lod评分标准，常规连锁分析（图2，顶部曲线）也排除了与H-ras-1的连锁（0< 0.095），并得出估计的重组分数为0.500。我们的系谱在几个方面不同于基廷等人分析的大犹他州系谱。（三）、一个区别是种族;因为直到近代，不同的犹太种族群体都倾向于作为相对孤立的群体生活，所以在他们的基因库中可能存在与其他群体不同的特定遗传缺陷。第二，在以色列血统中有几个近亲婚姻。虽然近亲繁殖造成了连锁分析的计算负担，但我们能够保留系谱中五个近亲繁殖循环中的四个。只有一个近亲繁殖的循环，在第三代，已经被打破。不考虑的主要后果是
0 Fig. 2. Profile lod functions for linkage of H-ras-1 to LOT. Bottom curve shows lod scores from combined linkage and segregation analy-sis (0= 0.494). Top curve shows lod scores from conventional linkage analysis (8= 0.500). completely dominant allele (7). We used this major locus and the H-ras-1 marker in a combined linkage and segregation analysis. This analysis (Fig. 2, bottom curve) shows that the major LQT locus is not tightly linked to H-ras-1 for the family in our study. The best estimate of the recombination fraction is 0.494, which is close to the value of0. 50 that corresponds to no linkage. Linkage can be excluded fore< 0.13 by conventional exclusion criteria (lod score of-2.0, which corresponds to a P value of 0.0024) or for 0< 0.23 by chi-square with P= 0.05. Second, for comparison with the results of Keating et al.(3), we performed conventional linkage analysis using their assumptions (dominant disease allele with a frequency of 0.001 and 0.9 penetrance) and their phenotypic definition. The use of their phenotypic definition, which is slightly different from the definition used by us (Table 1), resulted in a change in the status of 18 individuals from our studied pedigree, 17 from unaffected to equivocal, and one from affected to equivocal. Conventional linkage analysis (Fig. 2, top curve) also excludes linkage to H-ras-1 for 0< 0.095 according to the lod score criterion and yields an estimated recombination fraction of 0.500. Our pedigree differs in several ways from the large Utah pedigree analyzed by Keating et al.(3). One difference is ethnicity; because different Jewish ethnic groups tended to live as relatively isolated populations until recent times, specific genetic defects might be expected in theirgene pool that are different from those in other popula-tions. Second, in the Israeli pedigree there are several consanguineous marriages. Although inbreeding creates a computational burden for linkageanalysis, we were able to retain four of the five inbreeding loops in the pedigree. Only one inbreeding loop, in the third generation, has been broken. The major consequence of not accounting for