DISEASE VARIABILITY IN PATIENTS WITH CFTR GENE MUTATIONS

CF疾病的范围和严重程度是极不相同的。我们对大量明确定义的“典型”和“非典型”CF疾病以及疑似CF患者的评估，旨在阐明包括不同CFTR基因突变和其他调节性遗传因素在内的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疾病谱。同样，具有相同基因型（和特定器官）的患者之间CF疾病表达的一些变异性将是由于“修饰”基因变异对患者基因组的影响。此应用程序的具体目标是：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：常规诊断的CF，“非典型”CF和疑似患有CF的患者。定义CFTR基因突变的、经常规诊断标准诊断或具有“非典型”CF表型（包括男性不育症和特发性胰腺炎患者）的CF疾病的自然史。确定CFTR基因突变在具有类似CF的疾病表型（包括哮喘、慢性肺病和免疫反应性胰蛋白酶原高且汗液试验正常的新生儿）的队列中的频率。评估具有不同CFTR基因突变的专性杂合子，以寻找CF表型的证据。在上述患者队列中，确定不同CFTR基因突变和修饰基因对CF表型的相对影响。综上所述，我们将有助于澄清CF疾病的诊断，最终，我们的发现将导致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.