A cystic fibrosis transmembrane conductance regulator splice variant with partial penetrance associated with variable cystic fibrosis presentations

Some patients express various features of cystic fibrosis (CF) even though essential characteristics of the disease might be absent. Such patients may suffer from respiratory disease without pancreatic insufficiency and normal sweat chloride levels. Others may present as male infertility because of congenital bilateral aplasia of the vas deferens (CBAVD) with no other signs of CF. The 5T allele, a DNA variant in a noncoding region of the cystic fibrosis transmembrane conductance regulator (CFTR) gene that reduces the level of the normal CFTR transcripts, was found in increased frequency among male patients with CBAVD. The purpose of this study was to investigate the possibility that the 5T allele is associated with dysfunction of organs other than the male reproductive system, leading to CF or atypical CF. Analysis of the 5T allele was performed on 148 subjects (29 with CF, 61 with atypical CF, and 58 with CBAVD) carrying 232 chromosomes with unidentified CFTR mutations, and on 142 non-CF chromosomes from healthy subjects of Ashkenazi origin. The frequency of the 5T allele among chromosomes from patients of Jewish Ashkenazi origin with CF and atypical CF (six of 33; 18%) was significantly higher than the frequency in the normal Ashkenazi population (eight of 142; 6%; p = 0.03). Analysis of the clinical presentation of the five patients with CF and the 12 patients with atypical CF carrying the 5T allele indicated that most patients suffered from respiratory disease presenting as asthma like symptoms, nasal polyposis, chronic sinusitis, chronic bronchitis, or bronchiectasis. Six patients had pancreatic insufficiency, two with meconium ileus. Sweat Cl- levels ranged from normal to elevated. Of the six male patients with respiratory disease who were old enough to be evaluated for fertility status, five were fertile and one had pancreatic insufficiency. Among male patients with CBAVD, 41% suffered from respiratory symptoms. Thus, the 5T allele is a variant with partial penetrance causing disease with an extreme variability of clinical presentation: from normal healthy fertile subjects or male patients with CBAVD to those with atypical or typical clinical phenotype of CF.