CFTR genotypes in patients with normal or borderline sweat chloride levels

Abstract

In recent years, some patients bearing "atypical" forms of cystic fibrosis (CF) with normal sweat chloride concentrations have been described. To identify the spectrum of mutant combinations causing such atypical CF, we collected the results of CFTR (ABCC7) mutation analysis from 15 laboratories. Thirty patients with one or more typical symptoms of the disease associated with normal or borderline sweat chloride levels and bearing two CFTR mutations were selected. Phenotypes and genotypes of these 30 patients are described. A total of 18 different CFTR mutations were observed in the 60 chromosomes analysed. F508del was present in 31.6 % of the mutated chromosomes and 3849+10kbC>T in 13.3 %. R117H, D1152H, L206W, 3272-26A>G, S1235R, G149R, R1070W, S945L, and the poly-T tract variation commonly called IVS8-5T were also observed. The relative frequency of CFTR mutations clearly differed from that observed in typical CF patients or in CBAVD patients with the same ethnic origin. A mild genotype with one or two mild or variable mutations was observed in all the patients. These findings improve our understanding of the distribution of CFTR alleles in CF with normal or borderline sweat chloride concentrations and will facilitate the development of more sensitive CFTR mutation screening.

CFTR mutation distribution among U.S. Hispanic and African American individuals: Evaluation in cystic fibrosis patient and carrier screening populations

“…Each of these variable mutations has been reported in the literature in individuals with a diagnosis of cystic fibrosis, CAVD, and in unaffected carriers of 2 mutations. 15,24,25,34 Geographic differences in the origin of the carrier versus patient referrals may also contribute to the variation in mutation distributions between the groups. The lack of detection in the carrier screening population of mutations identified among patients (e.g., 2307delA, W1089X) is not unexpected given the inherent variability in estimates of low-frequency mutations.…”

“…In the carrier screening group, 4 mutations, D1152H, R117H, ⌬I507, and L206W, had frequencies of 3.8% to 6.2%, whereas the same mutations were either observed only once or not at all in the CF patient population. With the exception of ⌬I507, each of these mutations is associated with variable phenotypic expression [21][22][23][24][25][26] and when paired with ⌬F508 has been reported in individuals with cystic fibrosis as well as CAVD. 24 African American CF patient population Table 2 depicts the distribution of 33 CFTR mutations identified in the African American population.…”

“…Twelve mutations identified in the carrier screening population were not identified among the CF patient population. These include mutations known to be associated with variable phenotypic expression such as R117H, 21,22 D1152H, [23][24][25] and 3849ϩ10kbCϾT. 27,28 Assuming Ϸ74% detection for the mutations analyzed and an observed carrier frequency of 1/95, an adjustment to 100% detection would result in a carrier frequency of 1/76, which is not significantly different than the expected 1/61 3 based on the disease incidence (P ϭ 0.1779).…”

Classic Respiratory Disease but Atypical Diagnostic Testing Distinguishes Adult Presentation of Cystic Fibrosis

“…5,15,20,21 and is correlated with normal or indeterminate sweat chloride tests. 15,20,22 We surmise that the higher incidence of rare mutations in patients diagnosed as adults may contribute to the delay in diagnosis. In our study, 11% of patients diagnosed as adults with sweat tests reported had normal sweat chloride levels and 13.6% had intermediate levels, thus falling into the previously termed "nonclassic" CF defi nition.…”

Premarital and prenatal screening for cystic fibrosis: Experience in the Ashkenazi Jewish population

“…22 The D1152H/⌬F508 genotype also has been reported in four adults with mild pulmonary symptoms, two with Pseudomonas colonization, and another with pancreatic insufficiency. 23,24 This mutation has also been observed in males with CBAVD. 25,26 However, this mutation was present along with G542X in a fetus with hyperechogenic bowel loops and meconium ileus, suggesting a more severe course would occur in this case.…”