Rationale: Limited knowledge exists on phenotypes associated with the D1152H cystic fibrosis transmembrane conductance regulator (CFTR) mutation.Objectives: To characterize phenotypes in subjects with a D1152H allele in trans with another CFTR mutation.Methods: D1152H subjects were identified using the French Cystic Fibrosis (CF) Registry.Phenotypic characteristics were compared with those of CF subjects in the Registry (Controls).Main Results: Forty two subjects with D1152H alleles were identified.Diagnostic features included chronic sinopulmonary disease (n = 25), congenital absence of the vas deferens (n = 11), systematic neonatal screening (n = 4), and genetic counseling (n = 2).Excluding systematic neonatal diagnosis, median age at diagnosis was 33 (interquartile range, [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41]) yr in D1152H subjects and was 0.58 [0.17-3.67]yr in Controls (P < 0.001).Median sweat chloride concentrations were 43.5 [39-63] mmol/l in D1152H subjects vs. 100 mmol/l in Controls (P < 0.001).Only 10/42 (24%) D1152H subjects had classic CF.Nonclassic CF (sweat chloride 60 mmol/l and compatible clinical manifestations) was present in 26/42 (61.9%)D1152H subjects; 6/42 (14.3%)D1152H subjects were asymptomatic.Bronchiectasis was present in 67% of D1152H subjects, but Pseudomonas aeruginosa colonization and pancreatic insufficiency were present in <30% of subjects.Estimated rates of decline in FEV1 and in FVC were lower in D1152H subjects vs. Controls (P < 0.001).None the D1152H subjects identified since 1999 died or had lung transplantation despite an elevated age at last evaluation.Conclusions: D1152H is a mutation that when present in trans with a CF-causing mutation causes variable phenotypes, often characterized by nonclassic (mild) cystic fibrosis.Supported by: Vaincre la Mucoviscidose 18 Cystic Fibrosis and mitochondrial gene mutation MT-RNRI

The neonatal screening protocol for cystic fibrosis (CF) is based on a first determination of blood immunoreactive trypsin (IRT1), followed by a first level genetic test that includes the 31 worldwide most common mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (DNA31), and a second determination of blood immunoreactive trypsin (IRT2). This approach identifies, in addition to affected subjects, a high proportion of newborns with hypertrypsinaemia at birth, in whom only one mutation is identified and who have a negative or borderline sweat test and pancreatic sufficiency. Although it has been suggested that hypertrypsinaemia may be caused by a single CFTR mutation, whether such neonates should be merely considered as healthy carriers remains a matter of debate as hypertrypsinaemia at birth may be a biochemical marker of a CFTR malfunction because of a second mild mutation. We analyzed, by means of an extended sequencing protocol, 32 newborns who tested positive at an IRT1/DNA31/IRT2 screening protocol and in whom only one CFTR mutation was found. The results obtained demonstrate that 62.5% of these newborns were also carrying a second mild CFTR mutation. The high proportion of compound heterozygous subjects, combined with the results of a 4‐year follow‐up in nine of these subjects all of whom displaying initial CF clinical symptoms, suggest that it may be possible to use the IRT1/DNA31/IRT2 protocol of neonatal screening to identify newborns with atypical forms of CF. In view of these findings, an extended genetic search for subjects with compound heterozygosity and a periodic clinical assessment should be considered.