A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation

Abstract

Purpose: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. Genet Med 2010:12(9):548 -555.

Genotype–phenotype correlation and functional studies in patients with cystic fibrosis bearing CFTR complex alleles

“…We found the p.Leu997Phe homozygous or in trans with a known causing mutation either in patients with CFTR-RD (mainly CBAVD) or in healthy subjects, in agreement with previous reports 20 21 47. Furthermore, some of our subjects, classified as CFSPID in infancy, resulted free from symptom during the follow-up in the successive years, again in agreement with previous studies 48.…”

A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis

“…The three actually discrepant alleles were L997F (p.Leu997Phe), without the R117L (p.Arg117Leu) in cis, L206W (p.Leu206Trp) and T338I (p.Thr338Ile). The L997F (p.Leu997Phe) allele can, according to the findings that emerge both from this work and previous studies (28), also give rise to CF-PS, whereas in the CFTR2 study, it was classified as non-CFcausing. The L206W (p.Leu206Trp), which in our study was classified as a CFTR-RD-causing mutation, was classified as CF-causing in the CFTR2 study.…”

“…The (28) was found in 6 patients (1 CF-PI and 5 CF-PS). These patients had the following mutations on the other allele: F508del (p.Phe508del) (1 CF-PI), G85E (p.Gly85Glu) (1 CF-PS), R334W (p.Arg334Trp) (2 CF-PS siblings) and W1282X (p.Trp1282*) (2 CF-PS).…”

“…It is reasonable to assume that this transition is more likely to be influenced by intragenic (CFTRdependent) variability. It may originate from the large number of sequence variations and be markedly enhanced by their combination in trans and in cis as complex alleles (1,28), as well as by a regulatory posttranscriptional and posttranslational impairment that often escapes recognition. The second step may be defined as the transition from the CFTR protein residual function to clinical phenotype (residual functionality → clinical step).…”

Benign outcome among positive cystic fibrosis newborn screen children with non-CF-causing variants

“…22 In another example, the combination of R117L and L997F on the same allele causes a more severe phenotype than L997F alone, though this combination was not observed in this study. 23 There could be other reasons that CF cases with non CF-causing variants exist, including incomplete genotyping of the CFTR gene and gene-gene interactions.…”