Complex allele [-102T > A+S549R(T > G)] is associated with milder forms ofcystic fibrosis than allele S549R[T > G) alone

We recently reported a novel complex allele in the cystic fibrosis transmem brane regulator (CFTR) gene, combining a sequence change in the minimal CFT R promoter (-102T>A) and a missense mutation in exon 11 [S549R(T>G)]. Here we compare the main clinical features of six patients with cystic fibrosis (CF) carrying the complex allele [-102T>A+S549R(T>G)] with those of 16 CF p atients homozygous for mutation S549R(T>G) alone. Age at diagnosis was high er, and current age was significantly higher (P = 0.0032) in the group with the complex allele, compared with the S549R/S549R group. Although the prop ortion of patients with lung colonization was similar in both groups, the a ge at onset was significantly higher in the group with the complex allele ( P = 0.0022), Patients with the complex allele also had significantly lower sweat test chloride values (P = 0.0028) and better overall clinical scores (P = 0.004), None of the 22 patients reported in this study had meconium il eus. All 16 patients homozygous for S549R(T>G), however, were pancreatic in sufficient, as compared with 50% of patients carrying the complex allele (P = 0.013). Moreover, the unique patient homozygous for [-102T>A+S549R(T>G)] presented with a mild disease at 34 years of age. These observations stron gly suggest that the sequence change (-102T>A) in the CFTR minimal promoter could attenuate the severe clinical phenotype associated with mutation S54 9R(T>G).