DISEASE VARIABILITY IN PATIENTS WITH CFTR GENE MUTATIONS

CF疾病的范围和严重程度是极其异质性的。我们对大量明确定义的“典型”和“非典型”CF疾病患者以及疑似CF患者的评估，阐明了遗传因素（包括不同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疾病谱。同样，具有相同基因型的患者之间（以及在特定器官中）CF疾病表达的一些变异性将是由于“修饰物”遗传变体对患者基因组的影响。本申请的具体目的是：通过在明确定义的患者队列中鉴定CFTR基因突变来定义CF表型，所述患者队列具有：CF的常规诊断、“非典型”CF和那些疑似患有CF的患者。.定义CFTR基因突变患者CF疾病的自然史，这些患者通过常规诊断标准诊断或具有“非典型”CF表型，包括不育男性和特发性胰腺炎患者。.确定具有类似CF的疾病表型的队列中CFTR基因突变的频率，包括哮喘、慢性肺病和具有高免疫反应性胰蛋白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的CF表型证据。.在上述患者组群中，确定不同CFTR基因突变和修饰基因对CF表型的相对影响。总之，我们将有助于明确CF疾病的诊断，最终，我们的研究结果将莱亚诊断和治疗的重大进展。

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.