Copyright ©The Author(s) 2017.
World J Med Genet. Feb 27, 2017; 7(1): 1-9
Published online Feb 27, 2017. doi: 10.5496/wjmg.v7.i1.1
Table 1 Cystic fibrosis transmembrane conductance regulator mutation classes and cystic fibrosis personalized therapy.
Mutation classFunctional effectStructural defectMutation-specific interventionPersonalized therapy
IDefective protein synthesis (complete lack of protein production)Nonsense mutationsRestore synthesis by suppressors of premature stop codons in-frame (read-through drugs)Suppressor in phase 3 trials: Ataluren
Frameshift mutations
Severe splicing mutations
Deletions or insertions (a common mechanism is the onset of premature stop codons)
IIDefective protein processing and/or trafficking (severe decrease of protein in the apical membrane due to processing and/or maturation defects)Missense mutations Small deletions or insertionsRestore processing and trafficking by correctors (chemical, molecular, pharmacological chaperones) and combined approaches (corrector + potentiator)Combined therapy to patients: Orkambi (the corrector Lumacaftor + the potentiator Ivacaftor)
IIIDefective channel regulation and/or gating (impaired channel opening)Missense mutationsRestore channel regulation and gating by potentiatorsPotentiator to patients: Ivacaftor
Small deletions or insertions
IVDefective Cl- conductance (reduced Cl- transport through the channel)Missense mutationsRestore the Cl- conductance by potentiatorsUnder evaluation
Small deletions or insertions
VReduced mRNA synthesis (reduction of the wild type mRNA)Partial splicing mutations Promoter mutationsRestore wild-type mRNA levels by correctors, potentiators and/or antisense oligonucleotidesUnder evaluation
VIDecreased protein stability in membrane or reduced ability of other channel regulationMissense mutationsRestore stability and regulation ability by potentiators, stabilizers and/or suppressors of overdue stop codons in-frameUnder evaluation
Nonsense mutations
Frameshift mutations (a common mechanism is the onset of overdue stop codons because of mutations of the protein C-terminus)
Table 2 Comparison of classic and next generation sequencing approaches for diagnostic mutation search in cystic fibrosis.
FeatureClassic approachNGS approach
Analytical requirements for a full characterization of the CFTR geneMultiple technical steps and different analytical platformsReduced number of technical steps and single analytical platform
Data elaborationMultiple data elaboration steps handled by the laboratory itselfReduced number of data elaboration steps often performed by internal dedicated personnel or external structures
TimingTime consumingRapid
Cost per sampleHighLow (if a reasonably high number of samples are processed in the same run)
No. of mutations analyzedProgressively increasing from moderate (first steps) to high (last steps)High
Detection rateProgressively increasing from moderate (first steps) to high (last steps)High
Possibility to analyze other genes involved in the modulation of CF clinical manifestationsUnlikelyRealistic
FeatureClassic approachNGS approach