Considerations in using linkage analysis as a presymptomatic test for Huntington's disease.
Considerations in using linkage analysis as a presymptomatic test for Huntington's disease.
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DOI：
10.1136/jmg.25.9.577
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发表时间：
1988-09
影响因子：
4
通讯作者：
Lindsay A. Farrer;Richard H. Myers;Adrienne Cupples;A. P. M. Conneally
中科院分区：
文献类型：
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作者：
Lindsay A. Farrer;Richard H. Myers;Adrienne Cupples;A. P. M. Conneally
与亨廷顿氏病（HD）基因座遗传连锁的多态基因座D4 S10使得对那些有风险的人进行症状前测试成为可能。由于这种逐渐衰弱和致命的疾病的症状通常要到成年后才显现出来，因此测试的结果将影响有关职业、婚姻和生育的重大决定。如果HD在至少一个家庭成员中没有得到证实，则在使用测试之前必须考虑几种鉴别诊断。对大量系谱的审查表明，40%的高危人群没有合适的家庭结构进行连锁测试。此外，不合作或无法接近的亲属可能使这项测试不可行的许多其他人谁希望被测试。连锁相，这必须是已知的受影响的父母为一个信息测试，可以确定使用一个或多个12探针-酶组合D4 S10。尽管任何一个RFLP的多态性信息含量（PIC）值小于40%，但是两个G8 HindIII、pK 083 EcoRI和R7 BglII RFLP的单倍型的PIC值大于88%。我们已经开发了一个计划，将连锁数据和发病年龄的信息调整为删失的观察，受影响的父母的性别，和发病年龄的家族相关性，使用计算机程序MLINK计算HD的风险。模拟实验表明，适当的发病年龄调整是计算风险概率的关键。一个正式的症状前测试协议，包括测试前和测试后的咨询，心理测试和亲子鉴定建议。在几个实际的测试案例中说明了许多这些注意事项。
The polymorphic locus D4S10 that is genetically linked to the locus for Huntington's disease (HD) has made possible a presymptomatic test for those at risk. Because the symptoms of this progressively debilitating and fatal illness are not usually manifest until adulthood, the outcome of the test will influence major decisions about career, marriage, and procreation. Several differential diagnoses must be considered before using the test if HD is not confirmed in at least one family member. Review of a large number of pedigrees has shown that 40% of persons at risk do not have appropriate family structure for a linkage test. Furthermore, uncooperative or inaccessible relatives may make this test infeasible for many others who wish to be tested. Linkage phase, which must be known in the affected parent for an informative test, can be determined using one or more of 12 probe-enzyme combinations for D4S10. Although the polymorphism information content (PIC) value for any one RFLP is less than 40%, the PIC value for the haplotype of the two G8 HindIII, pK083 EcoRI, and R7 BglII RFLPs is greater than 88%. We have developed a scheme to incorporate linkage data and age at onset information adjusted for censored observations, sex of affected parent, and familial correlation for age at onset, using the computer program MLINK for calculation of risk of having HD. Simulated experiments showed that proper age at onset adjustment is crucial to the calculation of the probability of risk. A formal presymptomatic testing protocol, including pre- and post-test counselling, psychological testing, and paternity testing is recommended. Many of these considerations are illustrated in several actual test cases.