DNA Linkage Studies of Degenerative Retinal Diseases

描述（由申请人提供）：本持续项目的目的是鉴定导致常染色体显性视网膜色素变性（adRP）的基因和突变。像其他形式的遗传性视网膜疾病一样，AdRP是一组复杂的疾病，具有多种原因，不同的症状和不同的后果。例如，已知17个不同基因的突变会导致adRP。然而，已知基因中的突变占adRP家族的不到60%，因此在遗传水平上理解adRP之前还有很长的路要走。 我们的目标是确定影响其余40%家庭的基因和突变。我们假设其余病例将由1）新型adRP基因突变和2）标准筛查方法未检测到的已知基因突变或未被认为是致病性的突变引起。同样清楚的是，一些患有“adRP”的家庭实际上具有更复杂的遗传模式，即，双基因或X连锁显性疾病。挑战在于如何突破这一复杂性，以确定导致最大比例病例的基因。 为了实现这一目标，我们已经建立了一个逐步的，系统的方法来确定病人，突变检测，连锁图谱，和候选基因筛选。患者和家属通过我们的临床合作者确定并参加我们的研究。我们评估每个病人和家庭，选择最有效的分期测试，以确定潜在的基因和突变。患者和家属在随后的每个阶段都要重新评估。合适的家庭成为我们不断增长的具有良好特征的adRP家庭的一部分，现在有215个。先证者的DNA通过快速筛选方法进行检测，以检测已知adRP基因中的常见突变。那些没有突变的人成为一个不断扩大的样本组的一部分，用于发现新的疾病基因和已知基因中的新突变。 招募具有多个可接近的受影响个体的家庭进行连锁图谱分析，以检测与已知显性RP基因的连锁（以发现早期未检测到的突变），如果排除已知基因，则进行全基因组连锁检测（以发现新的adRP基因）。这些家庭是我们的“基因发现队列”。我们目前的一套连锁标记显性RP基因的目标是所有已知的基因和位点，几个额外的候选基因，和X-连锁基因，可能会导致临床症状的载体女性。全基因组连锁检测将使用Affyssin GeneChip Human Mapping 10 K Array通过SNP分型进行，该产品可通过德克萨斯大学医学博士安德森癌症中心微阵列核心设施（Houston，Texas）获得。 最后，来自家族的先证者如果不足以进行连锁作图，则成为我们“突变检测小组”的一部分。随着新基因的发现，或新的检测方法的出现，该小组被筛选以复制发现，确定患病率，并评估新概念。

DESCRIPTION (provided by applicant): The purpose of this continuing project is to identify the genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). AdRP, like other forms of inherited retinal disease, is a complex set of disorders, with multiple causes, variable symptoms, and differing consequences. For example, mutations in seventeen distinct genes are known to cause adRP. However, mutations in the known genes account for less than 60% of adRP families, thus there is a long way to go before adRP is understood at a genetic level. Our goal is to identify the genes and mutations affecting the remaining 40% of families. We hypothesize that the remaining cases will be caused by 1) mutations in novel adRP genes and 2) mutations in known genes that are not detected by standard screening methods or mutations that are not recognized as pathogenic. It is also clear that some families with "adRP" actually have more complex modes of inheritance, i.e., digenic or X-linked dominant disease. The challenge is to cut through this complexity to identify the genes that cause the largest fraction of cases. To achieve this goal we have established a step-wise, systematic approach to patient ascertainment, mutation testing, linkage mapping, and candidate gene screening. Patients and families are ascertained through our clinical collaborators and enrolled in our studies. We evaluate each patient and family to select the most effective staging of tests to determine the underlying gene and mutation. Patients and families are re-evaluated at each subsequent stage. Suitable families become part of our growing cohort of well-characterized adRP families, now numbering 215. DNAs from probands are tested by rapid screening methods to detect common mutations in known adRP genes. Those without mutations become part of an expanding panel of samples for finding new disease genes and novel mutations in known genes. Families with multiple, accessible, affected individuals are enrolled for linkage mapping to test for linkage to known dominant RP genes (to uncover mutations not detected earlier) and, if the known genes are excluded, for genome-wide linkage testing (to find new adRP genes). These families are our "Gene Discovery Cohort". Our current set of linkage markers for dominant RP genes is targeted to all of the known genes and loci, several additional candidate genes, and X-linked genes which may cause clinical symptoms in carrier females. Genome-wide linkage testing will be done by SNP typing using the Affymetrix GeneChip Human Mapping 10K Array, available through the Univ. of Texas MD Anderson Cancer Center Microarray Core Facility, Houston, Texas. Finally, probands from families that are not large enough for linkage mapping become part of our "Mutation Testing Panel". As new genes are identified, or as new approaches to testing become available, this panel is screened to replicate findings, determine prevalences, and evaluate new concepts.