The frequency and clinical significance of the S1235R mutation in the Cystic Fibrosis Transmembrane Conductance Regulator gene: results from a collaborative study

Abstract

More than 850 mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene have been reported to the Cystic Fibrosis (CF) Consortium. A missense mutation, S1235R, was originally reported in a CF patient with a second mutation (G628R) on the same chromosome. The clinical significance of S1235R was not clear. S1235R is not among the commonly reported mutations, and it is not routinely screened for in most laboratories. However, we have identified this variant in our laboratories at a higher frequency than many of the other CF mutations. Among more than 3,000 patients tested for either a possible diagnosis of CF or to determine CF carrier status, we identified 50 patients heterozygous for S1235R. No patients were homozygous for S1235R. The allele frequency of S1235R in this population (∼1%) was higher than that of the G551D or G542X CF mutations. Patients found to carry S1235R ranged in age from 1 day to 73 years. Indications for testing included rule out CF (15 cases), prenatally diagnosed echogenic bowel (2 cases), meconium ileus/obstruction at birth (3 cases), carrier screening with a positive family history (11 cases), carrier screening with a negative family history (17 cases) and unknown (2 cases). Four patients were compound heterozygotes for a second CFTR mutation: 2 cases (one family) were N1303K/S1235R and 2 unrelated cases were AF508/S1235R. Clinical data on those patients will be presented. No patient tested so far (N=31) carried the G628R CFTR mutation.

Our data suggests that S1235R, when combined with a second CF mutation, may be pathogenic, although phenotypic manifestations appear to be variable. However, the possibility that this represents a rare polymorphism cannot be discounted completely. Genetic counseling issues are difficult when S1235R is identified, even in the presence of a second known mutation, especially in prenatal cases.