Cystic Fibrosis Gene Mutations Research Articles

Insights Into Cystic Fibrosis Gene Mutation Frequency, Clinical Findings, and Complications Among Pakistani Patients.

Background Cystic fibrosis (CF) is a genetic disorder with diverse symptoms. Understanding its genetic basis and prevalence is crucial for effective management and treatment. Objective The study aimed to provide comprehensive insights into the frequency of CF gene mutations, clinical presentations, and complications among the Pakistani population. Methodology A cohort comprising 892 patients, ranging in age from 18 to more than 40 years, was selected on the basis of clinical and genetic criteria for the diagnosis of CF. Polymerase chain reaction (PCR) was used to look for 34 variants in the CFTR gene in blood samples. Statistical analysis, which included figuring out the number of mutations, the average age of diagnosis, and the genetic diversity of the samples, was performed to analyze the percentage of patients with specific mutations, offering insights into the genetic diversity. Results In our comprehensive analysis of 892 patient samples, 77.47% (n=691) displayed consanguinity, indicating a family history. The prevailing symptoms included chronic cough (88.67%; n=791), recurrent respiratory infections (76.68%; n=684), and fatigue (73.76%; n=658). The major complications comprised pulmonary infections (22%; n=197), cystic fibrosis-related diabetes (21%; n=187), and malabsorption (20%: n=178). A paired t-test revealed a mean difference of 5.750 with a standard deviation of 9.147, a 95% confidence interval from -0.061 to 11.561, a t-value of 2.178 with 11 degrees of freedom, and a two-tailed p-value of 0.052, suggesting a potential trend towards significance. Nevertheless, the asymptotic significance values of 1.000 and 0.998 for both groups indicate no significant difference. Furthermore, the study identified 12 cystic fibrosis gene mutations, with F508del and N1303K being the most prevalent. Conclusion This research revealed significant consanguinity, confirmed typical CFsymptoms, and identified common complicationsand prevalent CFTR gene mutations (with F508del and N1303K being the most common), providing insights for genetic guidance and treatment in the Pakistani community.

A review of cystic fibrosis: Basic and clinical aspects.

Cystic fibrosis is an autosomal recessive disease caused by mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Here we summarize, at the basic descriptive level, clinical and genetic characteristics of cystic fibrosis gene mutations, while emphasizing differences between CF mutations found in Chinese pediatric CF patients compared to those found in Caucasian CF patients. In addition, we describe animal models used to study human cystic fibrosis disease and highlight unique features of each model that mimic specific human CF‐associated signs and symptoms. At the clinical level, we summarize CF clinical manifestations and diagnostic, treatment, and prognostic methods to provide clinicians with information toward reducing CF misdiagnosis and missed diagnosis rates.

Ion concentrations in nasal airway surface liquid: a prediction model for the identification of cystic fibrosis carriers.

Cystic fibrosis (CF) carriers seem to have a higher risk to develop chronic rhino-sinusitis (CRS), although the full underlying mechanisms are unknown. Ion concentrations in nasal airway surface liquid (ASL) may be influenced by the heterozygosity for CF gene mutation, with possible impacts on the development of CRS. A cheap and feasible standardized technique was designed to measure the ion levels in nasal ASL. With this purpose we collected, under basal conditions, samples from the nasal cavity of 165 adults: 14 homozygous for CF, 83 carriers and 68 healthy controls. Sodium (Na) and Chlorine (Cl) concentrations were then evaluated among different groups. Statistical analysis revealed a significant difference of Na and Cl values between controls and carriers and between controls and homozygotes. Receiver operating characteristic (ROC) curves and derived indicators (Youden's index and Area Under the Curve, AUC) were used to further evaluate the diagnostic capability of Na and Cl concentrations to differentiate heterozygotes from controls. ROC curves demonstrated that the optimal diagnostic cut-off value of Na is at 124, and the optimal cut-off value of Cl is at 103,2. ASL sampling can be considered a new diagnostic tool for providing quantitative information on nasal ion composition. According to our findings, Na and Cl concentrations of nasal ASL could represent a useful tool to assess heterozygotes and healthy controls.

The Correlation of Cystic Fibrosis Mutations and Dental Caries in A Tertiary Care Center

Introduction: Previous data showed that dental caries is common in the Saudi general population as well as in the Cystic fibrosis patients. Objectives: to identify the correlation of dental caries severity with cystic fibrosis (CFTR) gene mutations in a tertiary care center Methodology: Retrospective cohort study through reviewing medical files for cystic fibrosis patients who had dental assessment during the period January 1998 to December 2018. Results: A total of 56 patients in group 1 (less than 12 years of age) and 55 patients for group 2 (more than 12 years of age). The score for dental caries (decay, missing and filled teeth) dmft/DMFT were 4.85 (4.6) for group 1 and 5.94 (4.27) for group 2. There were 3 common mutations in both groups namely in c.3700A>G, c.1418delG and c.1911delG. There is another common mutation in group 1 located in c.579+1G>T. Additionally, group 2 has another 3 common mutations that included c.416A>T, c.3909C>G, and c.1647T>G. Almost 95 % of mutations are in homozygous state in both groups. There was no single mutation that favors deterioration in DFMT score. Almost all mutations have similar scores, but certainly, group 2 has worse DFMT compared to group 1. There was no difference in dmft/DMFT scores between homozygous and heterozygous CFTR in both groups. Conclusion: No identified mutation that correlates with worsening in dental caries scores. There was no difference in dental caries’ scores between homozygous and heterozygous CFTR in both pediatric and adult groups

Cystic fibrosis gene mutations and polymorphisms in Saudi men with infertility.

ABSTRACTBACKGROUND: Some mutations of the cystic fibrosis transmembrane regulator (CFTR) gene may impair spermatogenesis or cause a congenital absence of the vas deferens that manifests as isolated male infertility.OBJECTIVE: Assess the frequency and analyze the spectrum of CFTR gene variations in Saudi men with primary infertility.DESIGN: Prospective, cross-sectional.SETTING: Tertiary care specialist hospital in Jeddah.PATIENTS AND METHODS: Genomic DNA was extracted from peripheral blood samples of Saudi men who presented with primary infertility to the outpatient andrology clinic with either azoospermia or oligoasthenoteratozoospermia. Polymerase chain reaction and direct sequencing were used to identify all variants of the CFTR gene.MAIN OUTCOME MEASURES: Proportion of the patients with a mutant CFTR gene and the spectrum of CFTR gene variations.SAMPLE SIZE: 50 infertile Saudi men.RESULTS: This study identified 10 CFTR gene variants in 7 (14%) subjects (100 chromosomes). The detected variants and polymorphisms were: c.1408G>A, c.4389G>A, c.2562T>G, c.869+11C>T, c.2909-92G>A, c.3469-65C>A, c.1210-6delT, c.1210-6T>A, c.2988+1G>A, and c.1210-13GT>TG.CONCLUSION: We demonstrated that 14% of the study subjects had one or more CFTR mutations and these were compounded in most of the affected patients. The spectrum of CFTR gene mutations in these subjects was similar to the mutations reported in other studies throughout the world.LIMITATIONS: Small sample size and the lack of a control group.CONFLICTS OF INTEREST: None.

Exercise and Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive, inherited congenital disease caused by the mutation of the family autosomal CF gene, with cumulative exocrine secretion characterized by inflammation, tracheal remodeling, and mucus accumulation. With the development of modern medical technology, CF patients are living longer lives and receiving more and more treatments, including traditional drugs, physical therapy, and gene therapy. Exercise is widely used to prevent and treat metabolic diseases such as cardiovascular diseases, obesity, diabetes, and metabolic syndrome. Regular exercise is beneficial to aerobic capacity and lung health. Exercise therapy has been of great interest since people realized that CF can be affected by exercise. Exercise alone can be used as an ACT (airway clearance technique), which promotes the removal of mucosal cilia. Exercise therapy is more easily accepted by any society, which helps to normalize the lives of CF patients, rather than placing a psychological burden on them. In this chapter, we will review the latest research progress about exercise in CF.

Universal strategy for preimplantation genetic testing for cystic fibrosis based on next-generation sequencing.

We developed and applied a universal strategy for preimplantation genetic testing for all cystic fibrosis gene mutations (PGT-CF) based on next-generation sequencing (NGS). A molecular protocol was designed to diagnose all CF mutations at preimplantation stage. The detection of CF mutations was performed by direct gene sequencing and linkage strategy testing 38 specific SNPs located upstream and inside the gene for PGT-CF. Seventeen couples at risk of CF transmission decided to undergo PGT-CF. Trophectoderm cell biopsies were performed on days 5-6 blastocysts. PGT for aneuploidy (PGT-A) was performed from the same samples. Tested embryos were transferred on further natural cycles. PGT was performed on 109 embryos. Fifteen CF mutations were tested. PGT-CF and PGT-A were conclusive for, respectively, 92.7% and 95.3% of the samples. A mean of 24.1 SNPs was informative per couple. After single embryo transfer on natural cycle, 81.3% of the transferred tested embryos implanted. The present protocol based on the entire CFTR gene sequencingtogether with informative SNPs outside and inside the gene can be applied to diagnose all CF mutations at preimplantation stage.

Universal strategy for preimplantation genetic testing for cystic fibrosis based on next generation sequencing

PurposeWe developed and applied a universal strategy for preimplantation genetic testing for all cystic fibrosis gene mutations (PGT-CF) based on next-generation sequencing (NGS).MethodsA molecular protocol was designed to diagnose all CF mutations at preimplantation stage. The detection of CF mutations was performed by direct gene sequencing and linkage strategy testing 38 specific SNPs located upstream and inside the gene for PGT-CF. Seventeen couples at risk of CF transmission decided to undergo PGT-CF. Trophectoderm cell biopsies were performed on day 5–6 blastocysts. PGT for aneuploidy (PGT-A) was performed from the same samples. Tested embryos were transferred on further natural cycles.ResultsPGT was performed on 109 embryos. Fifteen CF mutations were tested. PGT-CF and PGT-A were conclusive for respectively 92.7% and 95.3% of the samples. A mean of 24.1 SNPs was informative per couple. After a single embryo transfer on natural cycle, 81.3% of the transferred tested embryos were implanted.ConclusionsThe present protocol based on the entire CFTR gene together with informative SNPs outside and inside the gene can be applied to diagnose all CF mutations at preimplantation stage.

Outcome of non-visualization of fetal gallbladder on second-trimester ultrasound: cohort study and systematic review of literature.

To investigate the ultrasound characteristics and outcome of fetuses with non-visualization of the fetal gallbladder (NVFGB) followed in our tertiary university hospital, and to provide a comprehensive review of the literature on prenatal findings and outcome of NVFGB. NVFGB was defined as non-visualization of the gallbladder on two targeted ultrasound examinations performed within a 1-week period. First, we reviewed the medical records of NVFGB cases managed in our center over a 9-year period. Then, we performed a systematic review of the literature to identify studies on NVFGB. The incidence of chromosomal anomalies, later visualization of the gallbladder, gallbladder agenesis, cystic fibrosis and biliary atresia was assessed in fetuses with isolated and non-isolated NVFGB. The role of hepatic enzyme measurements in the diagnosis of cystic fibrosis and biliary atresia in fetuses with NVFGB was also reviewed. Sixteen cases of NVFGB were followed in our center, in 10 (62.5%) of which it was an isolated finding. The incidence of biliary atresia was 12.5% and that of gallbladder agenesis was 12.5%, while no case of cystic fibrosis was reported. The gallbladder was visualized later in pregnancy or postnatally in 43.8% and 25.0% of cases, respectively. A total of seven studies, including our cohort, involving a total of 280 NVFGB cases, met the inclusion criteria for the systematic review. Overall, 20.5% of fetuses had an associated ultrasound anomaly, and the incidence of chromosomal anomaly in this group was 20.4%. In cases with isolated NVFGB, the incidence of chromosomal anomaly was 1.9%. In fetuses with normal karyotype and isolated NVFGB, the gallbladder was later visualized in 70.4% of cases, while the incidence of gallbladder agenesis, cystic fibrosis and biliary atresia was 25.2%, 3.1% and 4.8%, respectively. In fetuses with non-isolated NVFGB, the incidence of cystic fibrosis and biliary atresia was 23.1% and 18.2%, respectively. The negative predictive value of amniotic fluid enzyme levels for the prediction of severe disease (including biliary atresia or cystic fibrosis) ranged between 94% and 100% when evaluated before 22 weeks' gestation, and dropped to 88% after 22 weeks. In cases with persistent NVFGB, the risk of a severe postnatal condition should be considered. A detailed ultrasound scan should be offered and parents tested for cystic fibrosis gene mutation. An invasive procedure for karyotyping and measurement of liver enzyme concentrations before 22 weeks constitutes a reasonable work-up. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

37 Depot Medroxyprogesterone Acetate in the Management of Recurrent Acute Pancreatitis in Patients With Cystic Fibrosis Gene Mutations

INTRODUCTION: In patients presenting with recurrent acute pancreatitis, cystic fibrosis (CF) gene variants are found at an increased frequency. Pancreatitis also occurs in patients being followed with CF mutations, generally occurring in patients with less severe mutations or in the setting of CF-related sorder (CFRD). There are no established treatment options for CF mutation-related pancreatitis. Some evidence has suggested that lung function fluctuates during the menstrual cycle, and in CF, that estradiol may inhibit chloride secretion. It has been hypothesized that hormonal contraceptives could play a role in modulating the disease process in women with CF. This study examined the impact of depot medroxyprogesterone acetate on the course of recurrent pancreatitis in female patients with established CF gene mutations. METHODS: In this single center retrospective study, medical records of all adult female patients with CF and acute recurrent pancreatitis between 2008–2018 were reviewed. Patients were included if they had experienced at least two episodes of acute pancreatitis, had been started on depot medroxyprogesterone, and had at least one CF gene mutation. Patients were excluded if they had developed pancreatitis from gallstones or heavy alcohol use. Total hospitalizations, episodes of pancreatitis, and average lipase values were examined and compared before and after the initiation of the depot medroxyprogesterone. RESULTS: A total of 13 patients met the study screening criteria and were recommended to start depot medroxyprogesterone. All patients were Caucasian females with a mean age of 45 years. The average time of treatment from which the endpoints were collected was 5.6 months. After the initiation of the depot medroxyprogesterone, there were no episodes of acute pancreatitis and one hospitalization unrelated to pancreatitis. The average lipase values were significantly decreased (261 units/L vs 41 units/L, P = 0.039) after the patients had been started on depot medroxyprogesterone. CONCLUSION: In this cohort, there were no further episodes of recurrent acute pancreatitis following the initiation of depot medroxyprogesterone in female patients with CF mutations. This data will be combined with other institutions shortly to examine the outcomes in a larger retrospective sample. A multicenter prospective study is being developed to study the outcomes being seen clinically and reported here in this sample.

P001 Phenotypic features of cystic fibrosis gene mutations in patients from the Russian Federation

P001 Phenotypic features of cystic fibrosis gene mutations in patients from the Russian Federation

Cystic Fibrosis Gene Mutation Frequency Among a Group of Suspected Children in King Hussein Medical Center.

Introduction:Cystic fibrosis (CF) is a genetic multisystem disorder that affects mostly the lungs, but other organs such as liver, pancreas and intestine also affected. CF is inherited in an autosomal recessive manner and occurs in males and females equally. Cystic fibrosis Transmembrane Conductance Regulator (CFTR) mutations are classified into five classes. Class 1 (non-functional protein), class 2 (near-absence of mature CFTR protein at the apical cell membrane), class 3 (full-length CFTR protein incorporated into the cell membrane), class 4 (reduced conductance CFTR mutation), and class 5 (reduced amount of CFTR protein with normal function). Globally F508 mutation is the most common.Aim:The aim of this study was to determine the frequency of CFTR gene mutation in Jordanian populations attending a major hospital (KHMC).Material and Methods:This is a retrospective study was conducted on 777 sera samples for patients clinically suspected to have cystic fibrosis over a six year period 1/1/2013-1/10/2018. The patient’s age range between 1year and 33 years, of which 59.2% (460) were male and 40.8% (317) female. Blood samples were analyzed at Princess Iman Centre for Research and Laboratory Sciences at King Hussein Medical Centre. The samples were tested for 34 mutations of CFTR gene using CF Strip Assay VIENNA LAB Diagnostics GmbH, Austria by polymerase chain reaction (PCR).Results:A total of 777 patients samples were analyzed for cystic gene mutations. Twelve (12) mutations were identified. In 49 patients (6.3%) were heterozygous genotype mutant and 28 (3.6%) were homozygous. The most frequent mutation F508del was found in 32/77 (41.5%). 20 (25.9%) of them were heterozygous genotype mutant and 12 (15.6%) were homozygous genotype mutant. The second frequent mutation was N1303K with frequency rate 15.6% (12/77), 9 (11.7%) of them were heterozygous and 3 (3.9%) were homozygous. Regarding frequency of cystic fibrosis gene mutation depending on sex, 55.8% (43/77) of mutations were found in male, whereas 44.2% (34/77) in female.Conclusion:Our findings suggest that cystic fibrosis in Jordan is not a rare disease, and found that the most frequent CFTR gene mutation was F508del, which is in keeping with results from other Mediterranean countries.

Innovative Therapies for Cystic Fibrosis: The Road from Treatment to Cure.

Cystic fibrosis (CF), a life-threatening multiorgan genetic disease, is facing a new era of research and development using innovative gene-directed personalized therapies. The priority organ to cure is the lung, which suffers recurrent and chronic bacterial infection and inflammation since infancy, representing the main cause of morbidity and precocious mortality of these individuals. After the disappointing failure of gene-replacement approaches using gene therapy vectors, no single drug is presently available to repair all the CF gene defects. The impressive number of different CF gene mutations is now tackled with different chemical and biotechnological tools tailored to the specific molecular derangements, thanks to the extensive knowledge acquired over many years on the mechanisms of CF cell and organ pathology. This review provides an overview and recalls both the successes and limitations of the different experimental approaches, such as high-throughput screening on chemical libraries to discover CF gene correctors and potentiators, dual-acting compounds, read-through molecules, splicing defect repairing tools, cystic fibrosis transmembrane conductance regulator (CFTR) "amplifiers," CFTR interactome modulators and the first gene editing attempts.

AGTR2 absence or antagonism prevents cystic fibrosis pulmonary manifestations

BackgroundPulmonary disease remains the primary cause of morbidity and mortality for individuals with cystic fibrosis (CF). Variants at a locus on the X-chromosome containing the type 2 angiotensin II receptor gene (AGTR2) were identified by a large GWAS as significantly associating with lung function in CF patients. We hypothesized that manipulating the angiotensin-signaling pathway may yield clinical benefit in CF. MethodsGenetic subset analysis was conducted on a local CF cohort to extend the GWAS findings. Next, we evaluated pulmonary function in CF mice with a deleted AGTR2 gene, and in those who were given subcutaneous injections of PD123,319, a selective AGTR2 antagonist for 12 weeks beginning at weaning. ResultsThe genetic subset analysis replicated the initial GWAS identified association, and confirmed the association of this locus with additional lung function parameters. Studies in genetically modified mice established that absence of the AGTR2 gene normalized pulmonary function indices in two independent CF mouse models. Further, we determined that pharmacologic antagonism of AGTR2 improved overall pulmonary function in CF mice to near wild-type levels. ConclusionsThese results identify that reduced AGTR2 signaling is beneficial to CF lung function, and suggest the potential of manipulating the angiotensin-signaling pathway for treatment and/or prevention of CF pulmonary disease. Importantly, the beneficial effects were not CF gene mutation dependent, and were able to be reproduced with pharmacologic antagonism. As there are clinically approved drugs available to target the renin-angiotensin signaling system, these findings may be quickly translated to human clinical trials.

Estimating Direct Cost of Cystic Fibrosis Care Using Irish Registry Healthcare Resource Utilisation Data, 2008-2012.

Understanding the determinants of cost of cystic fibrosis (CF) care and health outcomes may be useful for financial planning for the delivery of CF services. Registries contain information otherwise unavailable to healthcare activity/cost monitoring systems. We estimated the direct medical cost of CF care using registry data and examined how cost was affected by patient characteristics and CF gene (CF Transmembrane Conductance Regulator [CFTR]) mutation. Healthcare resource utilisation data (2008-2012) were obtained for CF patients enrolled with the Irish CF Registry by 2013 from linked registry and national hospitalisation database records. Mean annual hospitalisation and medication per-patient costs were estimated by demographic profile, CFTR mutation, clinical status, and CF co-morbidity, and were presented in 2014 euro values. A mixed-effects regression model was used to examine the effect of demographic, CFTR mutation, and clinical outcomes on the log10 cost of direct medical CF care. Using 4261 observations from 1100 patients, we found that the median annual total cost per patient increased over the period 2008-2012 from €12,659 to €16,852, inpatient bed-day cost increased from €14,026 to €17,332, and medication cost increased from €5863 to €12,467. Homozygous F508-CFTR mutation (class II) cost was highest and milder mutation (class IV/V) cost was 49% lower. Baseline estimated cost in 2008 for a hypothetical underweight, homozygous F508del-CFTR 6-year-old female without chronic Pseudomonas aeruginosa/Staphylococcus aureus, CF-related diabetes (CFRD) or methicillin-resistant S.aureus (MRSA), and with a poor percent predicted forced expiratory volume in 1s (ppFEV1) was €10,113, and was €21,082 in a 25-year-old with the same hypothetical profile. Chronic P. aeruginosa infection increased baseline cost by 39%, CF co-morbidity diabetes by 18%, and frequency of pulmonary exacerbation by 15%. Underweight, declining ppFEV1, chronic S. aureus colonisation, and time also influenced cost. CFTR mutation is an important factor influencing the cost of CF care. Costs differ among cohorts of CF patients eligible to access new and emerging CFTR repair therapies. These findings support the evaluation of outcome-associated cost in CFTR mutation-specific CF patient groups.

15 Analysis of cystic fibrosis gene mutations at national level in R. Macedonia

15 Analysis of cystic fibrosis gene mutations at national level in R. Macedonia

Electrochemical Determination of Cystic Fibrosis Gene Mutation by Magnetic Beads-Based Disposable Kit-type Biosensor

This paper introduces a disposable magnetic beads-based DNA biosensor for the rapid, sensitive and selective detection of Delta F508 (ΔF508del) Cystic Fibrosis (CF) gene mutation for the first time. The developed protocol contains the use of streptavidin-coated magnetic beads (MBs) and disposable screen printed carbon electrodes (SPEs). In the study, biotin-tagged specific capture probe was firstly immobilized on streptavidin-coated MBs and the modified beads were stored at 4°C in the form of a “kit” until the analysis of target DNA. The probe contained easy-constructed MBs kit was then incubated with the target DNA for hybridization. The detection of hybridization was identified based on enzymatic (alpha naphthol signal-based) or label-free (guanine signal-based) methods by using differential pulse voltammetry (DPV). The genosensor response was stable up to 6 months of storage period of the kit and the detection limit (LOD) of 0.5 picomole in 45 μL of sample volume was obtained for a 18-mer synthetic target with in 30 min detection time.

New and Emerging Treatments for Cystic Fibrosis.

Recently, a significant number of additional key medications have become licensed in Europe for the treatment of patients with cystic fibrosis (CF), including a number of inhaled antibiotics, such as nebulised aztreonam and dry powder versions of colistin and tobramycin for inhalation; dry powder inhaled mannitol, an agent to improve airway hydration and aid airway clearance; and ivacaftor, an oral therapy that directly acts on dysfunctional CFTR to correct the basic defect encountered in CF patients with the G551D CF gene mutation. The marked success of ivacaftor both in clinical trials and in post-licensing evaluation studies in treating patients with G551D and other gating mutations has greatly encouraged the ongoing development of similar therapies that can directly target the underlying cause of CF. Other therapies, including a number of anti-infectives, anti-inflammatories and replacement pancreatic enzymes, are currently undergoing clinical studies. This article reviews those treatments that have been recently licensed for CF and highlights some of the exciting emerging therapies presently under evaluation in clinical trials. In addition, it discusses some of the potential challenges being encountered by research and clinical teams in developing and delivering treatments for this condition.

9 Analysis of cystic fibrosis gene mutations in children with cystic fibrosis in a regional center in Eastern Romania

Objective The purpose of this study was to describe the genetic mutations identified in patients of pediatric age with cystic fibrosis (CF) diagnosed in a cystic fibrosis center in north-eastern Romania. Methods We performed a retrospective study which included 37 children with CF, followed between December 2012 and December 2014. In the absence of neonatal screening, diagnosis was based on sweat test in patients who presented respiratory or digestive clinical manifestations. The 32 patients (21 boys and 11 girls) involved were performed genetic tests only to identify 38 mutations using Real time PCR method. Results Following the genetic tests performed, there were identified: homozygous (F508del – 11 patients, G542X – 1 patient, 1898 + 1G>A – 1 patient), heterozygous compounds (F508del/G542X – 4 patients, F508del 7T/9T – 2 patients, F508del 9T/9T – 4 patients, D1152H 7T/7T – 1 patient) and other types of mutations 7T/7T – 8 patients. F508del mutation frequency was 65.62% in the study group. F508del mutation was associated with mixed forms (digestive and pulmonary) of CF in 13 patients and with pulmonary form of CF in 8 patients. Mutation 1898 + 1G>A was associated with a severe form of digestive disease and pulmonary of CF with unfavorable evolution. Conclusion F508del mutation frequency was similar compared to the frequency of this particular mutation in other European countries (70%). In Romania, it is necessary to introduce a genetic screening test for an early FC diagnosis and also for establishing the genetic profile of CF.

WS14.1 Ivacaftor improves exercise capacity in patients with G551D CF gene mutations

Introduction G551D is a CFTR mutation that results in impaired chloride channel function in Cystic Fibrosis (CF). Ivacaftor, a CFTR potentiating agent improves lung function and sweat chloride but its effect on exercise is unproven. Objectives To evaluate exercise capacity in response to correction of the chloride channelopathy with ivacaftor. Methods In a placebo-controlled crossover study of ivacaftor over 4 months with a 3 month open label extension we performed cardiopulmonary exercise tests (CPET) at six time points. 20 patients were included in the study. The primary outcome was VO2max as a percentage of baseline at the end of the crossover study (END X) and 3 month open label extension (OLE). A training program was not included in the study. Results There was a stepwise increase in maximal exercise capacity based on VO2max in the treated group above baseline at END X and 3 month OLE treatment periods. FEV1 and sweat chloride were also improved as expected. EndpointEnd X, mean (95% CI)OLE, mean (95% CI)%Δ absolute exercise time8.0 (1.4–14.6) * 12.1 (5.8–18.4) *** %Δ VO2max, ml/kg/min6.7 (2.7–10.8) ** 12.6 (6.3–18.9) *** %Δ VO2 ml/min7.8 (3.7–12.0) *** 15.6 (9.7–21.4) *** %Δ Watts5.0 (1.4–8.6) ** 10.9 (5.6–16.3) *** *p Conclusion Treatment of G551D patients with ivacaftor has a positive effect on exercise capacity which is independent of training. Improved VO2max has not been previously examined in clinical trials with ivacaftor and may have prognostic implications for patients with the G551D mutation. Supported by a grant from Vertex Inc.