Correspondence

Classification of CFTR
mutation classes
We read with great attention and
interest the Rapid Review by Kris
De Boeck and Margarida Amaral,1 who
suggested a new classification of cystic
fibrosis transmembrane regulator
(CFTR) mutations on the basis of
therapeutic strategies. The proposed
classification takes into account the
potential of personalised medicine
and targeted drugs in the treatment of
cystic fibrosis.
The development of new drugs (ie,
stabilisers, correctors, or potentiators)
based on CFTR gene mutation
classes 2 is a new and important
pharmacological model of precision
medicine3 with high financial costs,4
but the clinical responses so far are
variable. Many studies focusing on
clinical improvement of cystic fibrosis
symptoms through pharmacotherapy
include patients with coexisting severe
lung disease, which might mask the
true effects of the drug being tested.
Moreover, patients with the same CFTR
mutation genotype can have different
drug responses.2,5
The traditional classification
system categorises CFTR mutations
into six classes (figure). However,
De Boeck and Amaral 1 divided the
traditional class I mutations into
class I (stop-codon mutations) and a
new class VII (no mRNA transcription)
mutations. Class VII mutations
have the same outcome as class I
mutations—ie, absence of the CFTR
protein—but cannot be rescued by
corrective therapy. The classification
scheme suggested by De Boeck and
Amaral1 is important to improve the
development of new drugs. However,
in our opinion, their classification
does not take into account the
clinical severity of CFTR mutations
described in previous studies. In
their classification system, class VII
is the last mutation class in terms of
numerical order but is related to the
more severe mutation classes I, II,
and III, whereas classes IV, V, and VI
are associated with mild phenotypes
(figure).
Therefore, we propose a new
classification that will combine CFTR
defect, corrective therapy, and clinical
features associated with the mutations
(figure). In our proposal, the first CFTR
mutation class IA, which includes
mutations with severe phenotype Published Online
and no available corrective therapy, July 1, 2016
http://dx.doi.org/10.1016/
is followed by classes IB to VI. In our S2213-2600(16)30188-6
opinion, the inclusion of class VII is
necessary, but we propose renaming
this class as class I subtype A to allow
a continuous degree of severity across
the mutation classes, while retaining
De Boeck and Amaral’s idea.1 Having
such a logical classification will help
with the interpretation of the effects
of CFTR mutations and the choice of
personalised therapy.
New therapeutic approaches should
be made available for all patients
regardless of their CFTR mutation
classes. In the past 5 years, progress
has been made in bypass therapy,
cell-based therapy, and gene therapy,
making the search for an optimal
therapy one step forward.1,6–8
We believe that one classification
system will not be able to include
all information available (clinical
features, therapeutic strategies,
and CFTR defects). However, the
standard classification system
suggested here should allow

Traditional classification Class I Class II Class III Class IV Class V Class VI

Proposed classification Class IA Class IB Class II Class III Class IV Class V Class VI

De Boeck and Amaral’s Class VII Class I Class II Class III Class IV Class V Class VI
classification

CFTR defect No mRNA No protein No traffic Impaired gating Decreased Less protein Less stable
conductance

Mutation examples Dele2,3(21 kb), Gly542X, Phe508del, Gly551Asp, Arg117His, 3272-26A→G, c. 120del123,
1717-1G→A Trp1282X Asn1303Lys, Ser549Arg, Arg334Trp, 3849+10 kg rPhe580del
Ala561Glu Gly1349Asp Ala455Glu C→T

Corrective therapy Unrescuable Rescue synthesis Rescue traffic Restore channel Restore channel Correct splicing Promote
activity activity stability

Drugs (approved) Bypass therapies Read-through Correctors Potentiators Potentiators Antisense Stabilisers
(no) compounds (no) (yes) (yes) (no) oligonucleotides, (no)
correctors,
potentiators? (no)

Clinical features More-severe disease Less-severe disease

(global aspect)

Figure: CFTR mutations and therapeutic strategies in the traditional classification system, our proposed classification, and De Boeck and Amaral’s classification
Adapted from De Boeck and Amaral.1

www.thelancet.com/respiratory Vol 4 August 2016 e37

 Correspondence
improved communication among the
scientific community, patients, the
pharmaceutical industry, cystic fibrosis
societies, and the media.
We declare no competing interests.
*Fernando Augusto Lima Marson,
Carmen Sílvia Bertuzzo,
José Dirceu Ribeiro
fernandolimamarson@hotmail.com
Department of Pediatrics (FALM, JDR) and
Department of Medical Genetics (FALM, CSB),
Faculty of Medical Sciences, University of Campinas,
126 Cidade Universitária Zeferino Vaz, Campinas,
SP 13083-887, Brazil
e38
1 De Boeck K, Amaral MD. Progress in therapies
for cystic fibrosis. Lancet Respir Med 2016;
published online April 1. http://dx.doi.
org/10.1016/S2213-2600(16)00023-0.
2 Marson FAL, Bertuzzo CS, Ribeiro JD.
Personalized drug therapy in cystic fibrosis:
from fiction to reality. Curr Drug Targets 2015;
16: 1007–17.
3 Martiniano SL, Sagel SD, Zemanick ET.
Cystic fibrosis: a model system for precision
medicine. Curr Opin Pediatr 2016; 28: 312–17.
4 Ferkol T, Quinton P. Precision medicine:
at what price? Am J Respir Crit Care Med 2015;
192: 658–59.
5 Amaral MD. Novel personalized therapies for
cystic fibrosis: treating the basic defect in all
patients. J Intern Med 2015; 277: 155–66.
www.thelancet.com/respiratory Vol 4 August 2016
6 Shah VS, Ernst S, Tang XX, et al. Relationships
among CFTR expression, HCO3- secretion, and
host defense may inform gene- and cell-based
cystic fibrosis therapies. Proc Natl Acad Sci USA
2016; 113: 5382–87.
7 Suzuki S, Sargent RG, Illek B, et al.
TALENs facilitate single-step seamless SDF
correction of F508del CFTR in airway epithelial
submucosal gland cell-derived CF-iPSCs.
Mol Ther Nucleic Acids 2016; 5: e273.
8 Alton EWFW, Armstrong DK, Ashby D, et al.
Repeated nebulisation of non-viral CFTR gene
therapy in patients with cystic fibrosis:
a randomised, double-blind,
placebo-controlled, phase 2b trial.
Lancet Respir Med 2015; 3: 684–91.