Newborn screening programmes for cystic fibrosis

The Medical Journal of Australia, 2011

Saudi Medical Journal

Objectives: To investigate the geographic distribution of common cystic fibrosis )CF( variants in the western and southern regions of Saudi Arabia. : A retrospective study was conducted on 69 patients diagnosed with CF at King Faisal Specialist Hospital & Research Center, Jeddah. Patient data were collected retrospectively between June 2000 and November 2021. Various parameters were considered, including patient demographic information, CFTR variants, and respiratory cultures. Results: We identified 26 CFTR variants in 69 patients with CF, including one novel variant that had not been reported or published before )1549del G( in 2 patients with CF. The 6 most prevalentvariants Original Article were as follows: c.1521_1523delCTT )19%(, c.1418delG )10.2%(, c.579+1G>T )8.8%(, c.2988+1G>A )8.8%(, c.3419 T>A )7.2%(, and c.4124A>C )5.8%(. In addition, respiratory cultures revealed that Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae were highly common among patients with CF. This study highlighted features of patients with CF residing in the Western and Southern regions of Saudi Arabia. Six of the 26 CFTR variants were common in these patients. We also report, for the first time, a novel variant and other CFTR variants that are yet to be reported in Saudi Arabia. These findings could help establish a foundation for cystic fibrosis screening in Saudi Arabia and may assist in clinical diagnosis and prognosis.

European Journal of Human Genetics, 2002

The objective was to determine the composition of the Cystic Fibrosis (CF) Population attending specialist UK CF centres in terms of age, gender, age at diagnosis, genotype and ethnicity. With the planned introduction of the national CF screening programme in the UK, cystic fibrosis transmembrane regulator (CFTR) mutations were compared between different ethnic groups enabling a UK-specific frequency of mutations to be defined. Data were analysed from the patient biographies held in the UK CF Database (see www.cystic-fibrosis.org.uk). The currently registered population of 5274 CF patients is 96.3% Caucasian with a male preponderance that significantly increases with age. The majority of the 196 non-Caucasian CF patients are from the Indian Subcontinent (ISC), of which one in 84 UK CF patients are of Pakistani origin. The commonest CFTR mutation, DF508, is found in 74.1% of all CF chromosomes. In the Caucasian CF population, 57.5% are DF508 homozygotes but the UK ISC CF population with only 24.7%, has significantly fewer DF508 homozygotes patients (95% confidence interval (CI) 0.2-0.4). The distribution of Caucasian patients with DF508/DF508, DF508/Other and Other/Other does not fit the expected distribution with a Hardy-Weinberg model unless those patients without a detected mutation are excluded (P50.001). The UK CF Database has shown the UK CF population to have distinct characteristics separate from the North American and European CF Registries. The ISC group contains many mutations not recognised by current genetic analysis, and one in four ISC patients have no CFTR mutations identified. The CFTR analysis proposed for the screening programme would detect 96% of patients registered in the database, but is unlikely to achieve the desired 480% detection rates in the ethnic minority groups. Screen-positive, non-Caucasian infants without an identifiable CFTR mutation should be referred for a sweat test and genetic counselling when serum trypsinogen concentrations remain elevated after birth.

Journal of Cystic Fibrosis, 2007

Background: Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe. Method: A questionnaire was sent to 26 regional and national CF NBS programmes in Europe. Results: All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia™). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later. Conclusions: Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.

Pediatrics international : official journal of the Japan Pediatric Society, 2013

We performed a pilot study of neonatal screening for cystic fibrosis (CF) in order to introduce it to the national screening program in Serbia. Immunoreactive trypsinogen (IRT) concentrations were analyzed in dried blood spot samples. Patients were recalled for repeated measurements in case of high IRT levels. Persisting high IRT levels resulted in DNA testing for the 29 most common mutations in the CF transmembrane regulator (CFTR) gene (IRT/IRT/DNA method). Sweat chloride measurements and clinical assessment were further performed for newly diagnosed patients. Of 1000 samples, three were initially positive and were further analyzed for the presence of the most common CFTR mutations in the Serbian population. DNA analysis revealed two patients being homozygous for F508del mutation. One sample was false positive, as the genetic test proved to be negative and associated with normal sweat chloride concentration and unremarkable clinical presentation. The results of our pilot study justified the expanding of the routine neonatal screening program in Serbia with CF. Data could be used in future in order to obtain accurate incidence of CF and carrier prevalence in our country.

The Lancet, 2000

Journal of Cystic …, 2009

2020

Identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene and its numerous variants opened the way to fantastic breakthroughs in diagnosis, research and treatment of cystic fibrosis (CF). The current and future challenges of molecular diagnosis of CF and CFTR-related disorders and of genetic counseling are here reviewed. Technological advances have enabled to make a diagnosis of CF with a sensitivity of 99% by using next generation sequencing in a single step. The detection of heretofore unidentified variants and ethnic-specific variants remains challenging, especially for newborn screening (NBS), CF carrier testing and genotype-guided therapy. Among the criteria for assessing the impact of variants, population genetics data are insufficiently taken into account and the penetrance of CF associated with CFTR variants remains poorly known. The huge diversity of diagnostic and genetic counseling indications for CFTR studies makes assessment of variant diseas...

The Journal of pediatrics, 2005