DETERMINATION OF CYSTIC FIBROSIS MUTATION
FREQUENCY IN PRETERM AND TERM NEONATES
WITH RESPIRATORY TRACT PROBLEMS
Tanriverdi S1, Polat M, Onay H
*Corresponding Author: Sema Tanriverdi, M.D., Assistant Professor, Department of Pediatrics, Division
of Neonatology, Manisa Celal Bayar University Medical School, Uncubozkoy, 45030 Yunusemre,
Manisa, Turkey. Tel: +90-236-236-0330. Fax: +90-236-233-8040. E-mail: sema.tanriverdi@cbu.edu.tr
page: 25
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DISCUSSION
Cystic fibrosis is a multi-system disease affecting
lungs, gastrointestinal system, sweat glands and reproductive
system. It may lead to progressive respiratory failure
months, even years after birth [6]. Cystic fibrosis is caused
by mutations on a single large gene on chromosome 7,
which encodes the CFTR protein. Clinical disease requires
disease-causing mutations on both copies of the CFTR
gene. The CFTR database lists more than 2000 different
mutations on the CFTR gene that have the potential to cause
disease. The most common mutation is F508del [7,8]. The
CFTR gene sequencing should be done in cases with an
uncertain diagnosis. It should be performed in patients with
intermediate sweat chloride levels, and in patients with
confirmed or suspected CF if the genotype is not previously
known. In these patients, gene analysis confirms the
diagnosis and knowledge of the specific CFTR mutation
has important implications for treatment and prognosis [9-
11]. Links between genetic and phenotypic information in
CF are collected by an international consortium (Clinical
and Functional Translation of CFTR) and the results are
published on the consortium’s website (www.cftr2.org). At
the present time, information on specific phenotypic aspects
of hundreds of CFTR mutations have been reported. The
Cystic Fibrosis Mutation database lists more than 1500
different mutations in CFTR gene that have the potential
to cause disease (http://www.genet.sick kids.on.ca/cftr/).
Mutations of the CFTR gene have been divided into
five different classes. Class I mutations: defective protein
production, class II mutations: defective protein processing,
class III mutations: defective regulation, class IV mutations:
defective conduction, class V mutations: reduced
amounts of functional CFTR protein [12-14].
Clinical disease generally requires pathogenic mutations
on both copies of the CFTR gene, but individuals with
a single pathogenic variant (carrier status) occasionally
develop disease limited to one organ system. Clinical manifestations
of heterozygous carriers may include isolated
obstructive azoospermia, chronic rhinosinusitis, chronic
pancreatitis, pulmonary disease in adulthood or asymptomatic
[15,16]. There was no significant difference in CFTR
gene analysis in the control and patient groups (p = 0.340).
A c.1718C>T heterozygous mutation was detected
in an infant without respiratory distress. The c1718C>T
heterozygous mutation is phenotypically reported to result
in an elevated immunoreactive trypsinogen (IRT) in the
neonatal period (http://www.genet.sickkids.on.ca/cftr/).
In our case, the IRT screening test for the newborn was
reported as normal.
In two infants who had no respiratory distress in the
control group, a c.2421A>G heterozygous mutation was
detected. This has been evaluated as a polymorphism
found in the French population [17]. In the Cystic Fibrosis
Mutation Database, the c.2421A>G heterozygous mutation
has been reported in eight patients (http://www.genet.
sickkids. on.ca/cftr/). While one of them had asymptomatic
compound heterozygous mutation, a CFTR-related
disorder was detected in the remaining seven patients.
Congenital bilateral absence of vas deferens was found
in three of seven patients, chronic pancreatitis was found
in three cases and various clinical findings were detected
in one of the patients [17]. Patients with CFTR-related
disorders should be followed-up periodically. The estimated
prevalence and disease symptoms of individuals
with CFTR-related disorders may show changes in the
future [3,4]. Therefore, these two cases, who were not
symptomatic in the neonatal period, were enrolled for
follow-up.
A c.3683A>G heterozygous mutation was also found
in an infant who had no respiratory distress. This mutation
was reported in a 9-year-old Turkish girl by Kilinc et al.
in the Cystic Fibrosis Mutation Database in 2000 (http://
www.genet. sick kids.on.ca/MutationDetailPage.external?
sp=1084) This patient was diagnosed at age one and her
chloride level was <60 mEq/L in the sweat test and severe
respiratory findings along with bronchiectasis were
reported (http://www.genet.sickkids.on.ca/cftr/).
Another infant in the control group had a heterozygous
mutation c.650A>G. In the Cystic Fibrosis Mutation
Database, this mutation was detected in a 2-year-old Portuguese
male patient who had a sweat chloride concentration
of 60.0-80.0 mEq/L and had pancreatic insufficiency and
moderate lung disease [18]. This type of mutation was
also detected in one patient by Yoshimura et al. [19] in
1999 and it was reported that this patient had diffuse panbronchiolitis
findings.
A heterozygous mutation, c.1894_1895delAG, was
detected in one infant in the control group. There was no
reported case of this mutation in the literature review of
the CFTR gene analyses. No reported case of this mutation
was found in the Cystic Fibrosis Mutation Database.
A c.137C>A heterozygous mutation was detected
in an infant who had respiratory distress. This mutation
has so far been detected in patients with severe respiratory
symptoms and high chloride levels in the sweat test.
This mutation was found in two Greek patients with CF.
One of these patients was 18 years old, his sweat chloride
level was 80.0 mEq/L, respiratory function tests revealed
FEV1 58.0% and he had pseudomonas infections; the
other patient was 30 years old with a sweat chloride level
of 92.5 mEq/L, respiratory function tests revealed FEV1
92.5%, and he had pseudomonas infections and pancreatic
insufficiency [20]. A c.3935A>G heterozygous mutation was detected in
an infant in the patient group. In the Cystic Fibrosis Mutation
Database, this mutation was detected in a 14-year-old
male patient in 2008. He had a negative sweat test and
chronic sinusitis, pseudomonas-infected bronchitis, short
stature and growth retardation were reported in this patient
(http://www.genet.sickkids.on.ca/cftr/).
A c.4276T>C heterozygous mutation was found in
an infant in the patient group. In the Cystic Fibrosis Mutation
Database, this mutation was reported in a patient
with congenital bilateral absence of vas deferens in 1999
(http:// www.genet.sickkids.on.ca/cftr/).
A c.350G>C heterozygous mutation was found in an
infant in the patient group. This mutation is one of the 10
common mutations seen in CF (F508del, I507del, V520F,
G551D, G542X, R553X, R117H, 621+1G>T, N1303K,
A455E). The disease phenotype of this mutation can range
from asymptomatic to classic CF disease. Therefore, genetic
counseling is also challenging because of the phenotypic
changes associated with this mutation [21].
In this study, no significant difference was found in
the CFTR gene analysis in the newborns, with or without
respiratory distress in the neonatal period. A CFTR heterozygous
mutation was detected in 20.0% of the infants
with respiratory distress, while a CFTR gene heterozygous
mutation was found in 30.0% of the infants without respiratory
distress. This indicates that these infants who are not
symptomatic in the neonatal period should be followed-up
in terms of CFTR-related disorder and their families should
be informed. In this study, in an asymptomatic infant, a
heterozygous mutation c.1894_1895delAG (E632TfsX9)
was also detected on the CFTR gene. The heterozygous
mutation c.1894_1895delAG (E632TfsX9) is a novel mutation
and is reported in the literature for the first time.
Conclusions. This study demonstrates the importance
of CFTR gene analysis in asymptomatic newborn infants
for follow-up and early diagnosis of CFTR-related disorders
that may develop months or years after birth. In this
study, the c.1894_1895delAG (E632TfsX9) heterozygous
novel mutation was also detected in the CFTR gene, which
was first encountered in the literature in an asymptomatic
newborn infant. The limitations of this study was the low
number of patients.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This study was funded by Manisa Celal
Bayar University Scientific Research Projects Office [Project
#2015-133].
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