A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation.
OBJECTIVE
To evaluate the role of complex alleles, with two or more mutations in cis position, of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in the definition of the genotype-phenotype relationship in cystic fibrosis (CF), and to evaluate the functional significance of the highly controversial L997F CFTR mutation.


METHODS
We evaluated the diagnosis of CF or CFTR-related disorders in 12 unrelated subjects with highly variable phenotypes. According to a first CFTR mutational analysis, subjects appeared to be compound heterozygotes for a classic mutation and the L997F mutation. A further CFTR mutational analysis was conducted by means of a protocol of extended sequencing, particularly suited to the detection of complex alleles.


RESULTS
We detected a new [R117L; L997F] CFTR complex allele in the four subjects with the highest sweat test values and CF. The eight subjects without the complex allele showed the most varied biochemical and clinical outcome and were diagnosed as having mild CF, CFTR-related disorders, or even no disease.


CONCLUSIONS
The new complex allele partially explains the variable phenotype in CF subjects with the L997F mutation. CFTR complex alleles are likely to have a role in the definition of the genotype-phenotype relationship in CF. Whenever apparently identical CFTR-mutated genotypes are found in subjects with divergent phenotypes, an extensive mutational search is mandatory.
Lucarelli
Marco
M
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy. marco.lucarelli@uniroma1.it
Narzi
Lorena
L
Pierandrei
Silvia
S
Bruno
Sabina Maria
SM
Stamato
Antonella
A
d'Avanzo
Miriam
M
Strom
Roberto
R
Quattrucci
Serena
S
D000483:Alleles; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004252:DNA Mutational Analysis; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D010641:Phenotype
D019005:Cystic Fibrosis Transmembrane Conductance Regulator