Cystic fibrosis mutations and genotype–pulmonary phenotype analysis

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• 作者：Andrew T. Braun ; Philip M. Farrell ; Claude Ferec ; Marie Pierre Audrezet ; Anita Laxova ; Zhanhai Li ; Michael R. Kosorok ; Marjorie A. Rosenberg and William M. Gershan
• 刊名：Journal of Cystic Fibrosis
• 出版年：2006
• 出版时间：January 2006
• 年：2006
• 卷：5
• 期：1
• 页码：33-41
• 全文大小：176 K

文摘

Background

Although there are more than 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, most of them are uncommon and only limited information exists regarding genotype–pulmonary phenotype relationships.

Methods

We determined and classified the CFTR mutations using denaturing high-performance liquid chromatography and developed new, quantitative methods to categorize pulmonary phenotypes.

Results

Two novel alleles were discovered, namely G1047R and 1525-2A → G, which were accompanied by F508del and G551D mutations, respectively. Assessment of numerous options revealed that CF pulmonary phenotype categorization in children cannot be accomplished with clinical or pulmonary function data but is facilitated by longitudinal quantitative chest radiology. It was most useful to categorize pulmonary disease status by evaluating the typical pattern of abnormalities in patients homozygous for the F508del mutation, and then compare patients with minor mutations to this typical CF pulmonary phenotype. By this method, both patients with novel mutations have pulmonary phenotypes typical of F508del homozygotes. However, patients with class IV mutations (e.g., R347P) or with pancreatic sufficiency showed serial chest radiographs that were atypically mild.

Conclusions

Longitudinal quantitative chest radiography provides a new strategy for CF pulmonary phenotype categorization that should be useful for genotype–phenotype delineation in individual patients and in both epidemiologic studies and clinical trials involving groups of children with CF.