DNA Linkage Studies of Degenerative Retinal Diseases

描述(申请人提供)：这个持续项目的目的是确定导致常染色体显性遗传性视网膜色素变性(ADRP)的基因和突变。与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，已知基因的突变在ADRP家族中所占的比例不到60%，因此在基因水平上理解ADRP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)新的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确认为致病的突变引起。同样清楚的是，一些“adrp”家系实际上有更复杂的遗传模式，即双基因或X连锁显性疾病。挑战是要打破这种复杂性，找出导致最大比例病例的基因。 为了实现这一目标，我们已经建立了一种循序渐进的系统方法来确定患者、突变测试、连锁图谱和候选基因筛选。通过我们的临床合作者确定患者和家属，并加入我们的研究。我们评估每个患者和家庭，以选择最有效的测试阶段，以确定潜在的基因和突变。在随后的每个阶段，都会对患者和家属进行重新评估。合适的家庭成为我们日益增长的特征良好的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，以检测已知的adrp基因的常见突变。那些没有突变的人成为了不断扩大的样本小组的一部分，以寻找新的疾病基因和已知基因的新突变。 有多个可接触的受影响个体的家系被登记进行连锁作图，以测试与已知显性RP基因的连锁(以发现先前未检测到的突变)，如果排除已知基因，则进行全基因组连锁测试(以发现新的adrp基因)。这些家庭就是我们的“基因发现队列”。我们目前针对显性RP基因的连锁标记针对的是所有已知的基因和位点，几个额外的候选基因，以及可能导致女性携带者临床症状的X连锁基因。全基因组的连锁测试将通过使用Affymetrix基因芯片人类测绘10K阵列的SNP分型来完成，该阵列可通过大学获得。得克萨斯州休斯敦，德克萨斯州MD安德森癌症中心微阵列核心设施。 最后，来自不足以进行连锁作图的家庭的先证者将成为我们“突变检测小组”的一部分。当新的基因被识别，或者当新的检测方法可用时，这个小组被筛选以复制发现，确定流行率，并评估新的概念。

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.