ΔF508 Genotype Does Not Predict Disease Severity in an Ethnically Diverse Cystic Fibrosis Population

PEDIATRICS ◽  
1994 ◽  
Vol 93 (1) ◽  
pp. 114-118
Author(s):  
Lucille A. Lester ◽  
Jerome Kraut ◽  
John Lloyd-Still ◽  
Theodore Karrison ◽  
Carol Mott ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Ethnically Diverse ◽  
Clinical Parameter ◽  
Population Based ◽  
Age At Diagnosis ◽  
Chest Roentgenogram ◽  
Sweat Chloride ◽  
Cystic Fibrosis Population ◽  
Cftr Mutations

Objective. As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients. Methodology. We sought to examine the association between genotype as characterized by the ΔF508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications. Results. Age at diagnosis of CF was significantly associated with homozygosity for ΔF508 (mean age at diagnosis ± SE: 1.7 ± 0.3 years for ΔF508/ΔF508 vs 3.9 ± 0.9 years for ΔF508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with ΔF508 or any other genotype. Conclusion. These data suggest that in this sample of CF patients, ΔF508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci.

Population-based study of cystic fibrosis disease severity and haemochromatosis gene mutations

Respirology ◽  
2010 ◽  
Vol 15 (1) ◽  
pp. 141-149 ◽  
Author(s):  
Upasna PRATAP ◽  
Stephen QUINN ◽  
Leigh B. BLIZZARD ◽  
David W. REID
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Gene Mutations ◽  
Population Based ◽  
Population Based Study

scholarly journals Screening for the Most Common Mutations of CFTR Gene among Egyptian Children with Difficult-to-Treat Asthma

2020 ◽  
Vol 09 (03) ◽  
pp. 164-170
Author(s):  
Mohammad Al-Haggar ◽  
Engy Osman ◽  
Abdel-Rahman Eid ◽  
Tarek Barakat ◽  
Samar El-Morsi
Keyword(s):  
Cystic Fibrosis ◽  
Cftr Gene ◽  
Sweat Test ◽  
Amplification Refractory Mutation System ◽  
Single Mutation ◽  
Sweat Chloride ◽  
Increased Risk ◽  
Egyptian Children ◽  
Mutation System ◽  
Cftr Mutations

AbstractCystic fibrosis (CF) is panethnic autosomal recessive disease that affects the exocrine glands of pancreas, lungs, and intestine. It is often misdiagnosed in developing countries as difficult-to-treat asthma. We enrolled 150 Egyptian families with one or more probands who were complaining of difficult-to-treat asthma, and 112 cases were studied extensively through history taking including pedigree construction and clinical examination. In addition, spirometry and computed tomography of the chest were done in selected cases. All cases were subjected to quantitative sweat chloride test and molecular screening for the three most common mutations of cystic fibrosis transconductance regulator (CFTR) gene (ΔF508, G542X, W1282X) using amplification refractory mutation system (ARMS) technique. Probands of difficult-to-treat asthma comprised 66 males and 46 females; their age range was 1 to 14 years. Sixty-one probands (54.5%) were carriers of one or more of the studied mutations (36 cases and 25 carriers). Six carriers of single mutations had mild respiratory symptoms and negative sweat test. The most common allele was ΔF508, 60 alleles in 56 individuals (4 were homozygous ΔF508/ΔF508) followed by W1282X in 25 individuals and G542X in 12 individuals. Allele W1282X had an increased risk of recurrent chest infection and bronchiectasis. Moreover, cases with two mutations had more severe symptoms compared with those with a single mutation. CFTR mutations and CF-related syndromes are not rare as thought in Egypt, especially among the high-risk difficult-to-treat asthma. The readily available ARMS technique is recommended for ΔF508 and/or W1282X screening on priority basis among these children.

scholarly journals The frequency of heterozygous carriage of CFTR gene mutations causing the development of cystic fibrosis in a population-based cohort study (ESSE-Vologda)

2020 ◽  
pp. 64-65
Author(s):  
Е.А. Сотникова ◽  
М.В. Климушина ◽  
А.В. Киселева ◽  
О.П. Скирко ◽  
О.В. Курилова ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cohort Study ◽  
Real Time ◽  
Real Time Pcr ◽  
Gene Mutations ◽  
Population Based ◽  
System A ◽  
Cftr Mutations ◽  
Heterozygous Carriers ◽  
Custom Panel

Целью работы было создание панели для скрининга носительства мутаций, связанных с развитием муковисцидоза (МВ), и апробация панели в популяционной выборке ЭССЕ-Вологда. В исследование вошли 642 участника из популяционной выборки региона Вологды. Детекцию мутаций осуществляли с помощью системы QuantStudio 12K Flex Real-Time PCR. Создана скрининговая панель, включающая 60 мутаций гена CFTR. Среди 642 участников исследования выявлено 23 гетерозиготных носителя 6 мутаций, связанных с развитием МВ, частота носительства составила 3,58% (ДИ 95%: 2,28-5,33%) или 1:28 чеовек. Разработанная панель может быть использована для скрининга гетерозиготных носителей МВ. The aim of the study was to create a panel for screening the carriers of mutations associated with the development of cystic fibrosis (CF), and testing the panel on 642 participants of the population-based cohort study (ESSE-Vologda). Variants were detected using the QuantStudio 12K Flex Real-Time PCR system. A custom panel that includes 60 CFTR variants was created. Among 642 participants in the study, 23 heterozygous carriers of 6 CFTR mutations were identified. The carrier frequency was 3.58% (CI95%: 2.28-5.33%) or 1:28. The custom panel can be used for screening heterozygous CF carriers.

scholarly journals Stratifying infants with cystic fibrosis for disease severity using intestinal organoid swelling as a biomarker of CFTR function

2018 ◽  
Vol 52 (3) ◽  
pp. 1702529 ◽  
Author(s):  
Karin M. de Winter-de Groot ◽  
Hettie M. Janssens ◽  
Rick T. van Uum ◽  
Johanna F. Dekkers ◽  
Gitte Berkers ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Gastrointestinal Disease ◽  
Pancreatic Insufficiency ◽  
Chloride Concentration ◽  
Individual Level ◽  
Outcome Parameters ◽  
Sweat Chloride ◽  
Intestinal Organoids ◽  
Residual Capacity

Forskolin-induced swelling (FIS) of intestinal organoids from individuals with cystic fibrosis (CF) measures function of the cystic fibrosis transmembrane conductance regulator (CFTR), the protein mutated in CF.We investigated whether FIS corresponds with clinical outcome parameters and biomarkers of CFTR function in 34 infants diagnosed with CF. Relationships with FIS were studied for indicators of pulmonary and gastrointestinal disease.Children with low FIS had higher levels of immunoreactive trypsinogen (p=0.030) and pancreatitis-associated protein (p=0.039), more often had pancreatic insufficiency (p<0.001), had more abnormalities on chest computed tomography (p=0.049), and had lower z-scores for maximal expiratory flow at functional residual capacity (p=0.033) when compared to children with high FIS values. FIS significantly correlated with sweat chloride concentration (SCC) and intestinal current measurement (ICM) (r= −0.82 and r=0.70, respectively; both p<0.001). Individual assessment of SCC, ICM and FIS suggested that FIS can help to classify individual disease severity.Thus, stratification by FIS identified subgroups that differed in pulmonary and gastrointestinal outcome parameters. FIS of intestinal organoids correlated well with established CFTR-dependent biomarkers such as SCC and ICM, and performed adequately at group and individual level in this proof-of-concept study.

scholarly journals Two years of newborn screening for cystic fibrosis in North Macedonia: First experience

2021 ◽  
Vol 24 (1) ◽  
pp. 41-46
Author(s):  
S Fustik ◽  
V Anastasovska ◽  
D Plaseska-Karanfilska ◽  
A Stamatova ◽  
L Spirevska ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pilot Study ◽  
Newborn Screening ◽  
Chloride Concentration ◽  
Sweat Test ◽  
Sweat Chloride ◽  
Frequent Mutations ◽  
Cftr Mutations ◽  
The Republic ◽  
Cf Transmembrane Conductance Regulator

Abstract There is a widely accepted consensus on the benefits of newborn screening (NBS) for cystic fibrosis (CF) in terms of reduced disease severity, improved quality of life, lower treatment burden, and reduced costs. More and more countries in the world are introducing NBS for CF as a national preventive health program. Newborn screening for CF was introduced in the Republic of North Macedonia (RNM) in April, 2019, after a pilot study of 6 months in 2018. A two-step immunoreactive trysinogen (IRT-IRT) algorithm is performed, and then a sweat test for confirmation/exclusion of the CF diagnosis when the IRT values were both over the cutoff (70.0 and 45.0 ng/mL, respectively). In cases with confirmed diagnosis of CF (a sweat chloride concentration >60.0 mmol/L) or with intermediate sweat test results (a sweat chloride concentration of between 30.0 and 59.0 mmol/L), CF transmembrane conductance regulator (CFTR) mutation analysis is performed. By the end of 2020, over a period of 27 months, including the pilot study period, a total number of 43,139 newborns were screened for CF. Seventeen (0.039%) newborns were diagnosed with CF. In all newly discovered CF cases by screening, the diagnosis was confirmed by determination of the CFTR mutations. The most common CFTR mutation, F508del, was found with an overall incidence of 70.6%. Other more frequent mutations were G542X (11.8%) and N1303K (5.9%). Four mutations were found in one CFTR allele each: G1349D, G126D, 457TAT>G and CFTRdupexon22, with the last one being newly discovered with unknown consequences. An incredibly large difference was found in the incidence of the disease between the Macedonian and Albanian neonatal population, with almost four time higher prevalence among Albanians (1:4530 vs. 1:1284).

scholarly journals Lung function and disease severity in cystic fibrosis patients heterozygous for p.Arg117His

2017 ◽  
Vol 3 (1) ◽  
pp. 00056-2016 ◽  
Author(s):  
Michal Shteinberg ◽  
Damian G. Downey ◽  
Diane Beattie ◽  
John McCaughan ◽  
Alastair Reid ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Disease Severity ◽  
Pancreatic Insufficiency ◽  
Forced Expiratory Volume ◽  
Class I ◽  
Lung Function Decline ◽  
Diagnostic Features ◽  
Sweat Chloride ◽  
In Trans

Expression of p.Arg117His cystic fibrosis (CF) transmembrane conductance regulator is influenced by a polythymidine (poly-T) tract and a thymidine–guanine (TG) repeat on intron 9, which vary in length and affect exon 10 skipping.We compared clinical characteristics and the rate of progression of lung disease of CF patients carrying the p.Arg117His mutation with different intron 9 varying sequences (poly-T) and mutation classes in trans.Data were collected from patients in Northern Ireland, UK, including diagnostic features, sweat chloride, nutritional status, sputum microbiology, CF-related complications and lung function. Poly-T and TG repeats were determined by PCR. Forced expiratory volume in 1 s (FEV1) decline was determined from linear regression of FEV1 measurements of patients over time.We identified 62 patients with p.Arg117His, 55 with a class I/II mutation in trans and six with p.Arg117His/p.Gly551Asp. 42 patients had 5T and 13 had 7T. All patients had 12 TG repeats. Patients with p.Arg117His-5T had greater lung function decline, sweat chloride concentrations, pancreatic insufficiency and prevalence of Pseudomonas aeruginosa infection compared with patients with p.Arg117His-7T.Lung function decline and disease severity in p.Arg117His is determined by the poly-T tract length and identity of the mutation in trans. Patients with p.Arg117His-5T and a second class I/II mutation have a severity similar to p.Phe508del homozygous patients, although lung function decline is delayed to an older age. There may be linkage disequilibrium between p.Arg117His and 12 TG repeats.

scholarly journals Disease severity associated with cystic fibrosis mutations delta F508 and S549R [T-G]

2001 ◽  
Vol 7 (06) ◽  
pp. 975-980
Author(s):  
K. P. Dawson ◽  
P. M. Frossard ◽  
B. Al Awar
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
United Arab Emirates ◽  
Clinical Presentation ◽  
Clinical Severity ◽  
Biochemical Variables ◽  
Sweat Chloride ◽  
Severe Clinical Presentation ◽  
Age And Sex

We compared the clinical severity associated with the two cystic fibrosis [CF] mutations S549R [T [R] G] and deltaF508. Clinical and biochemical variables of CF were compared in two age- and sex-matched groups of CF children in the United Arab Emirates [UAE]. The clinical severity of mutations S549R [T [R] G] and delta F508 showed comparable patterns, with very low Shwachman scores and high sweat chloride levels. We conclude that patients homozygous for the CF mutations deltaF508 and S549R [T [R] G] have a severe clinical presentation and illness and are indistinguishable on clinical grounds.

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