Until the discovery of the gene for cystic fibrosis (CF) in 1989, diagnostic developments were limited, and treatment focused on symptom alleviation. However, following the genetic breakthrough, some 2,000 mutations of the gene have been identified. More recently CF transmembrane conductance regulator modulator triple therapy (CFTRm) has been introduced in the form of triple therapy with ivacaftor, lumacaftor and tezacaftor (ETI), in the United States from 2019, Europe from 2020 and then Australia from 2021. The new treatment option has revolutionised both the quality of life and life expectancy of many persons diagnosed with CF. This editorial reviews major developments in the clinical care that can now be provided to patients, and reflects on the legal and ethical ramifications of the improved situation for many patients in the contexts of medical negligence, damages assessment, family law and criminal law. It also considers the difficult issues of access and equity caused by the limited availability of the triple therapy in low- and middle-income countries.

BACKGROUND: In highly multiracial populations with inadequate newborn screening, knowledge of the various phenotypic presentations of Cystic Fibrosis (CF) can help reach an early diagnosis. This study aims to describe phenotypes and genotypes at the time of CF diagnosis in a state in the Northeast Region of Brazil.
METHODS: Retrospective cross-sectional study. Clinical data were extracted from the medical records of CF patients. Clinical, laboratory, and genotypic characteristics were described for patients admitted to a tertiary referral center between 2007 and 2021.
RESULTS: Fifty-eight (58) patients were included in the study, 53.5% of whom were diagnosed through clinical suspicion. The median age at diagnosis was 4.7 months (IQR: 1.5-14.8 months). Five patients had false-negative results in the newborn screening. Faltering growth was the most frequent clinical manifestation. Bronchiectasis and a history of pneumonia predominated in those older than ten, while thinness, underweight, and electrolyte imbalances were more frequent in children under two. Sequencing of the CFTR gene identified 27 genotypes, with at least one class I-III variant in all patients, and nine variants that are rare, previously undescribed, or have uncertain significance (619delA, T12991, K162Q, 3195del6, 1678del > T, 124del123bp, 3121-3113 A > T). The most frequent alleles were p.Phe508del, p.Gly542*, p.Arg334Trp, and p.Ser549Arg.
CONCLUSIONS: Malnutrition and electrolyte imbalances were the most frequent phenotypes for children < 2 years and were associated with genotypes including 2 class I-III variants. Rare and previously undescribed variants were identified. The p.Gly542*, p.Arg334Trp, and p.Ser549Arg alleles were among the most frequent variants in this population.

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Cystic fibrosis is a debilitating disease characterized by a poor medical prognosis due to devastating lung injury. Recent medical advances targeting the major genetic mutation ΔF508 of the cystic fibrosis transmembrane conductance regulator (CFTR) protein have dramatically increased the lifespan of patients with this mutation. This development has led to major changes in the field and has pushed research beyond the ion transport nature of cystic fibrosis and toward multiorgan physiological reprogramming. In this issue of the JCI, Bae, Kim, and colleagues utilized a large animal pig model prior to the onset of disease. They revealed metabolic reprogramming and organ crosstalk that occurred prior to disease progression. These findings provide paradigm-shifting insight into this complex disease.

AimsWe aimed to describe the clinical, economic, and societal burdens of cystic fibrosis (CF) and impact of CF transmembrane conductance regulator modulator (CFTRm) treatment on people with CF, caregivers, and healthcare systems.Material and MethodsThis retrospective study used linked real-world data from Swedish national population-based registries and the Swedish CF Quality Registry to assess clinical, economic, and societal burden and CFTR impact in CF. Records from people with CF and a ten-fold control population without CF matched by sex, birth year, and location were compared during 2019. Outcomes for a subset aged >6 years initiating lumacaftor/ivacaftor (LUM/IVA) in 2018 were compared 12 months pre- and post-treatment initiation.ResultsPeople with CF (n = 743) had >10 times more inpatient and outpatient specialist visits annually vs controls (n = 7406). Those aged >18 had an additional 77·7 (95% CI: 70·3, 85·1) days of work absence, at a societal cost of €11,563 (95% CI: 10,463, 12,662), while caregivers of those aged <18 missed an additional 6.1 (5.0, 7.2) workdays. With LUM/IVA treatment, people with CF (n = 100) had significantly increased lung function (mean change in ppFEV1 [3·8 points; 95% CI: 1·1, 6·6]), on average 0·5 (95% CI: -0·8, -0·2) fewer pulmonary exacerbations and 45·2 (95% CI: 13·3, 77·2) fewer days of antibiotics. Days of work lost by caregivers of people with CF aged <18 decreased by 5·4 days (95% CI: 2·9, 7·9).ConclusionCF is associated with a high clinical economic and societal burden in Sweden. Improvements in clinical status observed in people with CF treated with LUM/IVA were reflected in reduced caregiver and societal burden.
Cystic fibrosis (CF) is a disease caused by a single faulty gene called CFTR, which affects the lungs, pancreas, and other organs. Medications known as CFTR modulators help improve the function of this faulty gene and have shown benefits for people with CF. In Sweden, two such medicines, lumacaftor and ivacaftor (LUM/IVA), have been available since July 2018 for treating CF.This study looks at the impact of CF on patients, caregivers, and the healthcare system, as well as the benefits of CFTR modulators.Using data from Swedish national healthcare and social insurance registries, the study compared 743 people with CF in 2019 to about 7400 people without CF, matched by sex, birth year, and location.The findings show that people with CF had 24 times higher direct healthcare costs, including outpatient visits, hospitalizations, and CF-related medications, totaling 23,233 Euros. Indirect costs, such as work absences for those over 18 with CF and caregivers\' absences to care for sick children, were 9,629 Euros, which is five times higher than the general population. Those over 6 years old treated with LUM/IVA showed improved lung health, reduced hospitalizations (though not significantly), and needed fewer antibiotics. Caregivers\' work absences decreased, but there was no change in work absences for adults with CF. Overall, treatment with LUM/IVA improved clinical outcomes and reduced the burden on caregivers and society.

Cystic fibrosis (CF), also known as mucoviscidosis, is the most common autosomal recessive genetic disease in the Caucasian population, with an estimated frequency of 1:2000-3000 live births. CF results from the mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene localized in the long arm of chromosome 7. The product of CFTR gene expression is CFTR protein, an adenosine triphosphate (ATP)-binding cassette (ABC) transporter that regulates the transport of chloride ions (Cl-) across the apical cell membrane. Primary manifestations of CF include chronic lung and pancreas function impairment secondary to the production of thick, sticky mucus resulting from dehydrated secretions. It is well known that CF can cause both anterior and posterior ocular abnormalities. Conjunctival and corneal xerosis and dry eye disease symptoms are the most characteristic manifestations in the anterior segment. In contrast, the most typical anatomical and functional changes relating to the posterior segment of the eye include defects in the retinal nerve fiber layer (RNFL), vascular abnormalities, and visual disturbances, such as reduced contrast sensitivity and abnormal dark adaptation. However, the complete background of ophthalmic manifestations in the course of CF has yet to be discovered. This review summarizes the current knowledge regarding ocular changes in cystic fibrosis.

The Cystic Fibrosis Conductance Transmembrane Regulator gene encodes for the CFTR ion channel, which is responsible for the transport of chloride and bicarbonate across the plasma membrane. Mutations in the gene result in impaired ion transport, subsequently leading to perturbed secretion in all exocrine glands and, therefore, the multi-organ disease cystic fibrosis (CF). In recent years, several studies have reported on CFTR expression in immune cells as demonstrated by immunofluorescence, flow cytometry, and immunoblotting. However, these data are mainly restricted to single-cell populations and show significant variation depending on the methodology used. Here, we investigated CFTR transcription and protein expression using standardized protocols in a comprehensive panel of immune cells. Methods: We applied a high-resolution Western blot protocol using a combination of highly specific monoclonal CFTR antibodies that have been optimized for the detection of CFTR in epithelial cells and healthy primary immune cell subpopulations sorted by flow cytometry and used immortalized cell lines as controls. The specificity of CFTR protein detection was controlled by peptide competition and enzymatic Peptide-N-Glycosidase-F (PNGase) digest. CFTR transcripts were analyzed using quantitative real-time PCR and normalized to the level of epithelial T84 cells as a reference. Results: CFTR mRNA expression could be shown for primary CD4+ T cells, NK cells, as well as differentiated THP-1 and Jurkat T cells. In contrast, we failed to detect CFTR transcripts for CD14+ monocytes and undifferentiated THP-1 cells, as well as for B cells and CD8+ T cells. Prominent immunoreactive bands were detectable by immunoblotting with the combination of four CFTR antibodies targeting different epitopes of the CFTR protein. However, in biosamples of non-epithelial origin, these CFTR-like protein bands could be unmasked as false positives through peptide competition or PNGase digest, meaning that the observed mRNA transcripts were not necessarily translated into CFTR proteins, which could be detected via immunoblotting. Our results confirm that mRNA expression in immune cells is many times lower than in that cells of epithelial origin. The immunoreactive signals in immune cells turned out to be false positives, and may be provoked by the presence of a high-affinity protein with a similar epitope. Non-specific binding (e.g., Fab-interaction with glycosyl branches) might also contribute to false positive signals. Our findings highlight the necessity of accurate controls, such as CFTR-negative cells, as well as peptide competition and glycolytic digest in order to identify genuine CFTR protein by immunoblotting. Our data suggest, furthermore, that CFTR protein expression data from techniques such as histology, for which the absence of a molecular weight or other independent control prevents the unmasking of false positive immunoreactive signals, must be interpreted carefully as well.

Celocentesis is a new sampling tool for prenatal diagnosis available from 7 weeks in case of couples at risk for genetic diseases. In this study, we reported the feasibility of earlier prenatal diagnosis by celocentesis in four cases of cystic fibrosis and one case of cystic fibrosis and β-thalassemia co-inherited in the same fetus. Celomic fluids were aspired from the celomic cavity between 8+2 and 9+3 weeks of gestation and fetal cells were picked up by micromanipulator. Maternal DNA contamination was tested and target regions of fetal DNA containing parental pathogenetic variants of CFTR and HBB genes were amplified and sequenced. Four of the five fetuses resulted as being affected by cystic fibrosis and, in all cases, the women decided to interrupt the pregnancy. In the other case, the fetus presented a healthy carrier of cystic fibrosis. The results were confirmed in three cases on placental tissue. In one case, no abortive tissue was obtained. In the last case, the woman refused the prenatal diagnosis to confirm the celocentesis data; the pregnancy is ongoing without complications. This procedure provides prenatal diagnosis of monogenic diseases at least four weeks earlier than traditional procedures, reducing the anxiety of patients and providing the option for medical termination of the affected fetus at 8-10 weeks of gestation, which is less traumatic and safer than surgical termination in the second trimester.

Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl- and other anions. A dysfunctional CFTR due to abnormalities in the cftr gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme.

Cystic fibrosis (CF) is an autosomal recessive disease caused by the inheritance of two mutant cystic fibrosis transmembrane conductance regulator (CFTR) alleles, one from each parent. Autosomal recessive disorders are rarely associated with germline mutations or mosaicism. Here, we propose a case of paternal germline mutation causing CF. The subject also had an identifiable maternal mutant allele. We identified the compound heterozygous variants in the proband through Sanger sequencing, and in silico studies predicted functional effects on the protein. Also, short tandem repeat markers revealed the de novo nature of the mutation. The maternal mutation in the CFTR gene was c.1000C > T. The de novo mutation was c.178G > A, p.Glu60Lys. This mutation is located in the lasso motif of the CFTR protein and, according to in silico structural analysis, disrupts the interaction of the lasso motif and R-domain, thus influencing protein function. This first reported case of de novo mutation in Asia has notable implications for molecular diagnostics, genetic counseling, and understanding the genetic etiology of recessive disorders in the Iranian population.
Identifying the first de novo mutation in the cystic fibrosis transmembrane conductance regulator protein in Iran: a case report with insights from microsatellite markersA child can develop Cystic Fibrosis (CF) if both parents pass on mutated genes. In some rare cases, new genetic mutations occur spontaneously, causing CF. This report discusses a unique case where a child has one gene with a spontaneous mutation and inherits another gene mutation from the mother. We used a method called Sanger sequencing to find the two different gene changes in the affected person. We also used computer analysis to predict how these changes might affect the protein responsible for this genetic disease. To confirm that the child\'s new change is not inherited, we used a type of genetic marker called microsatellite markers. The mutation inherited from the mother and the new spontaneous mutation resulted in a unique change in the responsible protein. This mutation is located in a specific part of the protein called the lasso motif. Our computer simulations show that this mutation disrupts the interaction between the lasso motif and another part of the protein called the R-domain, which ultimately affects the protein\'s function. This case is significant because it is the first reported instance of a de novo mutation causing CF in Asia. It has important implications for genetic testing, counseling, and understanding how recessive genetic disorders like CF occur within the Iranian population.