DISEASE VARIABILITY IN PATIENTS WITH CFTR GENE MUTATIONS

CF病的范围和严重程度是非常不同的。我们对大量明确定义的“典型”和“非典型”CF病患者以及那些怀疑患有CF的患者进行了评估，以阐明遗传因素(包括不同的CFTR基因突变和其他调节遗传因素)对疾病表型的相对影响。我们的总体目标是全面了解与CFTR基因突变和/或变异相关的CF病的谱系。同样，在相同基因型别(以及特定器官)的患者之间，CF疾病表达的一些差异将是由于患者基因组上的“修饰”基因变异的影响。本申请的具体目的是：。通过在定义明确的患者队列中识别CFTR基因突变来定义CF表型，这些患者包括：CF的传统诊断、“不典型”CF和那些怀疑患有CF的患者。。明确CFTR基因突变患者的自然病史，这些患者按常规诊断标准诊断或具有“不典型”的CF表型，包括男性不育症和特发性胰腺炎患者。。确定疾病表型与CF型相似的队列中CFTR基因突变的频率，包括哮喘、慢性肺部疾病以及高免疫反应胰酶原和正常汗液试验的新生儿。。评估具有不同CFTR基因突变的专性杂合子，以寻找CF型的证据。。在上述患者队列中，确定不同的CFTR基因突变和修饰基因对CF表型的相对影响。综上所述，我们将有助于明确CF病的诊断，最终，我们的发现将有助于诊断和治疗方面的重大进展。

The range and severity of CF disease is extremely heterogeneous. Our evaluation of a large number of well defined patients with "typical" and "atypical" CF disease and those suspected of having CF are elucidating the relative influence on the disease phenotype of genetic factors including the different CFTR gene mutations and other modulatory genetic factors. Our overall goal is to establish a comprehensive understanding of the spectrum of CF disease associated with mutations and/or variants in the CFTR gene. As well, some variability in CF disease expression between patients with the same genotype (and in specific organs) will be due to the effects of "Modifier" genetic variants on a patient's genome. The specific aims of this application are to: . define CF phenotypes by identifying CFTR gene mutations in well defined patient cohorts with: a conventional diagnosis of CF, "atypical" CF and those suspected of having CF. . define the natural history of CF disease in patients with CFTR gene mutations who are diagnosed by conventional diagnostic criteria or have "atypical" CF phenotype including males with infertility and patients with idiopathic pancreatitis. . determine the frequency of CFTR gene mutations in cohorts with disease phenotypes resembling CF including asthma, chronic lung disease, and neonates with high immunoreactive trypsinogen and normal sweat test. . evaluate obligate heterozygotes with different CFTR gene mutations for evidence of CF phenotypes. . determine, in the above mentioned patient cohorts, the relative influence in the CF phenotype the different CFTR gene mutations and modifier genes. Taken together, we will help to clarify the diagnosis of CF disease and ultimately, our findings will lea to significant advances in diagnosis and therapy.