Kimberling William J
Center for the Study and Treatment of Usher Syndrome, Boys Town National Research Hospital and the Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, Nebraska 68131, USA.
Hum Mutat. 2005 Nov;26(5):462-70. doi: 10.1002/humu.20221.
The routine testing for pathologic mutation(s) in a patient's DNA has become the foundation of modern molecular genetic diagnosis. It is especially valuable when the phenotype shows genetic heterogeneity, and its importance will grow as treatments become genotype specific. However, the technology of mutation detection is imperfect and mutations are often missed. This can be especially troublesome when dealing with a recessive disorder where the combination of genetic heterogeneity and missed mutation creates an imprecision in the genotypic assessment of individuals who do not appear to have the expected complement of two pathologic mutations. This article describes a statistical approach to the estimation of the likelihood of a genetic diagnosis under these conditions. In addition to providing a means of testing for missed mutations, it also provides a method of estimating and testing for the presence of genetic heterogeneity in the absence of linkage data. Gene frequencies as well as estimates of sensitivity and specificity can be obtained as well. The test is applied to GJB2 recessive nonsyndromic deafness, Usher syndrome types Ib and IIa, and Pendred-enlarged vestibular aqueduct syndrome.
对患者DNA中的病理性突变进行常规检测已成为现代分子遗传学诊断的基础。当表型表现出遗传异质性时，它尤其有价值，并且随着治疗变得针对基因型，其重要性将不断增加。然而，突变检测技术并不完善，突变常常被遗漏。在处理隐性疾病时，这可能会特别麻烦，因为遗传异质性和遗漏的突变相结合，会导致对那些似乎没有预期的两个病理性突变组合的个体进行基因型评估时出现不精确性。本文描述了一种在这些情况下估计遗传诊断可能性的统计方法。除了提供一种检测遗漏突变的方法外，它还提供了一种在没有连锁数据时估计和检测遗传异质性存在的方法。还可以获得基因频率以及敏感性和特异性的估计值。该测试应用于GJB2隐性非综合征性耳聋、I型和IIa型Usher综合征以及Pendred - 扩大的前庭导水管综合征。
