Gamaletsou Maria N, Hayes Gemma, Harris Chris, Brock Joanna, Muldoon Eavan G, Denning David W
a The National Aspergillosis Centre , University Hospital of South Manchester, The University of Manchester and Manchester Academic Health Science Centre , Manchester , UK.
b Genomic Diagnostics Laboratory, Manchester Centre for Genomic Medicine , Central Manchester University Hospitals NHS Foundation Trust, St Mary's Hospital , Manchester , UK.
J Asthma. 2018 Aug;55(8):837-843. doi: 10.1080/02770903.2017.1373808. Epub 2017 Oct 16.
The F508del mutation occurs in approximately 3.5% of Caucasian population of Northern Europe. Heterozygotes have increased risk for asthma and reduced pulmonary function. Allergic bronchopulmonary aspergillosis (ABPA) is more common in patients with cystic fibrosis (CF). We aimed to establish the frequency of F508del mutation in adult patients with ABPA.
A retrospective matched case-control study of CF genotyped patients with ABPA seen at the National Aspergillosis Centre was undertaken. Key data were collected retrospectively from medical records, including respiratory comorbidities, total IgE, Aspergillus IgG and IgE, and immunoglobulins. Cystic fibrosis transmembrane regulator (CFTR) gene mutation analysis included multiplex PCR and sequencing.
From a cohort of 189 ABPA patients, 156 were screened for common mutations and variants in the CFTR gene. Eighteen were heterozygous for at least one CFTR mutation; 12 (7.7%) were heterozygous for the F508del, notably; 3 were heterozygous for the intron 8 5T variant; and 1 for an intronic variant of uncertain significance, c.3139 + 18C>T. Eight (67%) had asthma, 7 (58%) had CT-defined bronchiectasis, 4 (33%) hypergammaglobulinemia (>16 g/L), 3 (25%) sinusitis and 1 (8%) chronic pulmonary aspergillosis. Eight (67%) had elevated Aspergillus IgG antibodies (42-98 mg/L), and 8 (67%) had total IgE above 1,000 KIU/L. Two individuals heterozygous for the F508del mutation and the TG12T5 variant were diagnosed with CF, leading to a de novo CF discovery rate of 1.3%.
In our ABPA patient cohort, the presence of the delta F508 mutation was higher than that seen in general population. Genetic counseling for CFTR genotyping might be appropriate for these patients.
F508del突变在北欧约3.5%的白种人群中出现。杂合子患哮喘的风险增加且肺功能降低。变应性支气管肺曲霉病（ABPA）在囊性纤维化（CF）患者中更为常见。我们旨在确定成年ABPA患者中F508del突变的频率。
对在国家曲霉病中心就诊的CF基因分型的ABPA患者进行了一项回顾性匹配病例对照研究。关键数据从病历中回顾性收集，包括呼吸合并症、总IgE、曲霉IgG和IgE以及免疫球蛋白。囊性纤维化跨膜传导调节因子（CFTR）基因突变分析包括多重PCR和测序。
在189例ABPA患者队列中，对156例进行了CFTR基因常见突变和变异的筛查。18例至少有一种CFTR突变的杂合子；值得注意的是，12例（7.7%）为F508del杂合子；3例为内含子8 5T变异的杂合子；1例为意义不明的内含子变异c.3139 + 18C>T的杂合子。8例（67%）有哮喘，7例（58%）有CT定义的支气管扩张，4例（33%）有高球蛋白血症（>16 g/L），3例（25%）有鼻窦炎，1例（8%）有慢性肺曲霉病。8例（67%）曲霉IgG抗体升高（42 - 98 mg/L），8例（67%）总IgE高于1000 KIU/L。2例F508del突变和TG12T5变异的杂合子被诊断为CF，导致新发CF的发现率为1.3%。
在我们的ABPA患者队列中，δF508突变的存在高于一般人群。对这些患者进行CFTR基因分型的遗传咨询可能是合适的。
