Role of <Emphasis Type="Italic">CFTR</Emphasis> mutation analysis in the diagnostic algorithm for cystic fibrosis

Background:The cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation identification is being used with increased frequency to aid in the diagnosis of cystic fibrosis (CF) in those suspected with CF.Aim of this study was to identify diagnostic outcomes when CFTR mutational analysis was used in CF diagnosis.CFTR mutational analysis results were also compared with sweat chloride results.Methods:This study was done on all patients at our institution who had CFTR mutation analysis over a sevenyear period since August 2006.Results:A total of 315 patients underwent CFTR mutational analysis.Fifty-one (16.2％) patients had two mutations identified.Among them 32 had positive sweat chloride levels (≥60 mmol/L),while seven had borderline sweat chloride levels (40-59 mmol/L).An additional 70 patients (22.3％) had only one mutation identified.Among them eight had positive sweat chloride levels,and 17 had borderline sweat chloride levels.Fifty-five patients (17.5％) without CFTR mutations had either borderline (n=45) or positive (n=10) sweat chloride results.Three patients with a CF phenotype had negative CFTR analysis but elevated sweat chloride levels.In eighty-three patients (26.4％) CFTR mutational analysis was done without corresponding sweat chloride testing.Conclusions:Although CFTR mutation analysis has improved the diagnostic capability for CF,its use either as the first step or the only test to diagnose CFTR dysfunction should be discouraged and CF diagnostic guidelines need to be followed.     

Mild course of cystic fibrosis associated with heterozygosity for infrequent mutations in the first nucleotide-binding fold of CFTR

The mild clinical course of a patient with cystic fibrosis is presented who inherited the two mutations Gly551----Asp and Arg553----Stop in the cystic fibrosis transmembrane conductance regulator gene. The missense mutation Arg553----Stop discovered in American Blacks is also present on cystic fibrosis chromosomes of Caucasian ancestry.     

Newborn screening for cystic fibrosis in Alberta: Two years of experience

On April 1, 2007, Alberta became the first province in Canada to introduce cystic fibrosis (CF) to its newborn screening program. The Alberta protocol involves a two-tier algorithm involving an immunoreactive trypsinogen measurement followed by molecular analysis using a CF panel for 39 mutations. Positive screens are followed up with sweat chloride testing and an assessment by a CF specialist. Of the 99,408 newborns screened in Alberta during the first two years of the program, 221 had a positive CF newborn screen. The program subsequently identified and initiated treatment in 31 newborns with CF. A relatively high frequency of the R117H mutation and the M1101K mutation was noted. The M1101K mutation is common in the Hutterite population. The presence of the R117H mutation has created both counselling and management dilemmas. The ability to offer CF transmembrane regulator full sequencing may help resolve diagnostic dilemmas. Counselling and management challenges are created when mutations are mild or of unknown clinical significance.     

Inconclusive Cystic Fibrosis neonatal screening results: long-term psychosocial effects on parents

Aim:  Cystic Fibrosis (CF) Newborn Screening occasionally identifies neonates where a CF diagnosis can neither be confirmed nor excluded. To assess how parents of these infants cope with this ambiguous situation.
Methods:  Parents of 11 children with Ambiguous Diagnosis (group AD) were compared with parents of 11 children diagnosed with CF through neonatal screening [group Cystic Fibrosis Diagnosis (CFD)] and with parents of 11 Healthy Control children (group HC) matched for gender and age.
Results:  The emotional reaction to the inconclusive result was less pronounced in AD than in CFD (p = 0.003), and AD parents considered their infants as healthy as controls. Parents' anxiety about their child's health is stronger in CFD than in AD (p < 0.05) and HC (p < 0.001). Long-term emotional distress was rated similarly in AD and CFD, and greater than in HC (p = 0.0003). The parent/child relationship was less influenced in AD than in the CF group (p = 0.03). Seven AD and CFD parents changed their family planning projects.
Conclusion:  Inconclusive neonatal screening results appear to be understood and associated with lower anxiety levels than CF diagnosis. Concern about the child's health is similar to healthy controls and lower than in parents of CF children.     

Clinical papers of the year 2018 – Cystic fibrosis

This paper reviews the most important clinical papers in cystic fibrosis published in 2018, having searched all the literature on Pubmed. Focus is on CFTR modulator therapy, randomised controlled trials, and infection/microbiology issues.     

CFTR gene variants,epidemiology and molecular pathology

Pathogenic variants of the CFTR gene are responsible for a broad phenotypic spectrum characterized by malfunction of some exocrine tissues, with an autosomal recessive mode of inheritance. More than 2,000 variants, distributed throughout the CFTR gene, have been identified, with different effects on the gene and protein expression and function. Genotype-phenotype correlation studies have associated severe variants with a typical multi-organ form of cystic fibrosis, while mild variants are involved in monosymptomatic or adult-onset diseases, called CFTR-related disorders. However, the interpretation of rare variants remains challenging.This review presents an overview of the epidemiology of CFTR variants worldwide and in France and describes the functional classification. Finally, some frequent cystic fibrosis-causing and mild CFTR variants are used as example to depict the molecular pathology of the CFTR locus. Finally, we give the recommendations concerning nomenclature and classification that are useful for appropriate genetic counseling.© 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.     

CFTR modulator therapies – Effect on life expectancy in people with cystic fibrosis

CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes.     

Left behind: The potential impact of CFTR modulators on racial and ethnic disparities in cystic fibrosis

The advent of CFTR modulators, a genomic specific medication, revolutionized the treatment of CF for many patients. However, given that these therapeutics were only developed for specific CFTR mutations, not all people with CF have access to such disease-modifying drugs. Racial and ethnic minority groups are less likely to have CFTR mutations that are approved for CFTR modulators. This exclusion has the potential to widen existing health disparities.     

Genetics of cystic fibrosis: Basics

Cystic fibrosis (CF) is an autosomal recessive genetic disorder whose responsible gene – the CFTR gene – was discovered 30 years ago by a positional cloning strategy. This gene, which encodes a chloride channel, contains more than 2,000 mutations including a major one (p.Phe508del). This discovery has led to considerable progress in the understanding of the pathophysiology of CF as well as in the management of patients and their families. It has also paved the way for the development of specific therapies for the disease. From an epidemiological point of view, the incidence of CF, which shows loco-regional variations, is now estimated at 1/4,700 live births in France. The face of CF has dramatically changed over the past decades: CF has gradually become a disease of the adult with, today, more than 50% of the patients being 18 years old or more and a median predicted survival age that exceeds 45 years.© 2020 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.     

Restoration of exocrine pancreatic function in older children with cystic fibrosis on ivacaftor

Prior to the use of cystic fibrosis (CF) modulator therapy, exocrine pancreatic insufficiency in CF was thought to be irreversible. Improvement in pancreatic function on ivacaftor has been reported in open label studies in 1–5 year olds. The mechanism by which ivacaftor might improve exocrine pancreatic function is unclear. Although the effect of ivacaftor on pancreatic function may be more significant in younger children, evidence is mounting that there may still be potential for improvement in older children on long term therapy.     

Cystic Fibrosis: Advancing Along the Continuum

Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from a mutation in the gene which encodes a cellular transmembrane protein channel known as the CF transmembrane conductance regulator. Located systemically on the surface of numerous cells, these altered channels yield multisystem dysfunction. Typical manifestations seen are chronic, progressive, obstructive lung disease, pancreatic insufficiency, CF-related diabetes mellitus, malabsorption and malnutrition, liver disease, and infertility.Once considered a pediatric disorder, through developments in innovative care and therapeutic modalities, CF now spans the life continuum and has established itself as an ageless disease. Facing management of maturing-life issues, advanced practice nurses (APNs) in pediatrics now find themselves needing to collaborate with or facilitate transition of care to other APNs, such as nurse midwives and adult APNs, as well as their counterpart specialists in medicine, all while maintaining open communication with the patient, family and managing CF center.     

Recent advances in cystic fibrosis

Considerable advances in cystic fibrosis (CF) research have translated into improved patient care, reflected by a continuing trend of improving life expectancy in CF patients. This review summarises some of the major findings of CF research that have occurred in the past year. The review specifically focuses on those developments that have direct implications for patient care or those in which clinical trials suggest benefits that may impact on the treatment of CF patients in the near future.     

Sweat testing for cystic fibrosis: A review of New Zealand laboratories

BACKGROUND: Evolving diagnostic criteria for cystic fibrosis, broadening of the populations being tested and the need to interpret intermediate sweat test results have imposed a much greater need to standardize the collection and analysis of sweat. AIM: To identify variations in sweat testing in New Zealand laboratories and compare these with guidelines from the UK and the USA. METHODS: All laboratories in New Zealand offering sweat testing were identified and data collected from these laboratories by structured questionnaire. RESULTS: There were no New Zealand laboratories that conformed to either set of guidelines. Inconsistencies were observed in minimum sweat quantities, the nature of the iontophoresis solution, the sweat electrolytes analysed, quoted reference ranges and recommendations made as a consequence of the result. CONCLUSIONS: Conformity to the guidelines would help to minimize variation in sweat testing in New Zealand. Performance of a sufficient number of tests to maintain expertise is critical, but geographical constraints make patient travel to distant centres difficult in a small, scattered population. A possible solution, where numbers permit, may be the collection of sweat locally, with referral to a major laboratory for analysis. This is only possible with adequate training in collection and follow-up audit of the sweat testing procedure both in the collection and in the analytical phase.