• Genetic Carrier Screening
• Molecular Diagnostic Techniques
• Respiratory Tract Diseases

• Humans
• Cystic Fibrosis/genetics
• Cystic Fibrosis/diagnosis
• Cystic Fibrosis/epidemiology
• Australia/epidemiology
• Genetic Carrier Screening/methods
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Genetic Testing/methods
• Heterozygote
• Bayes Theorem
• Female
• Mutation
• Male

• targeted gene repair
• crispr-cas9 genome editing

• Humans
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Gene Editing/methods
• Epithelial Cells/metabolism
• HEK293 Cells
• Cystic Fibrosis/genetics
• Cystic Fibrosis/therapy
• RNA, Guide, CRISPR-Cas Systems/genetics
• CRISPR-Cas Systems
• Aminophenols/pharmacology
• Quinolones/pharmacology

• K99 HL163805 NHLBI NIH HHS
• P01 HL152960 NHLBI NIH HHS
• RM1 HG009490 NHGRI NIH HHS
• R00 HL163805 NHLBI NIH HHS
• P01HL152960 U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• R35GM118062 U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
• R35 GM118062 NIGMS NIH HHS
• Liu investigatorship Howard Hughes Medical Institute (HHMI)
• T32 GM008313 NIGMS NIH HHS
• UH3 HL147366 NHLBI NIH HHS
• RM1HG009490 U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
• U24 HG010423 NHGRI NIH HHS

• Base editing
• CRISPR–Cas
• Clinical treatment
• Gene and cell therapy
• Gene therapy delivery
• Genome editing
• Prime editing

• Humans
• Precision Medicine/methods
• Gene Editing/methods
• CRISPR-Cas Systems/genetics
• Translational Research, Biomedical
• Animals
• Genetic Therapy/methods

• 82471107 National Natural Science Foundation of China
• 31970930 National Natural Science Foundation of China
• 2020CFA069 Natural Science Foundation of Hubei Province
• 2018CFB434 Natural Science Foundation of Hubei Province

• Genomics
• Obstetrics
• Pregnancy

• Female
• Humans
• Pregnancy
• Cystic Fibrosis/genetics
• Cystic Fibrosis/therapy
• Ehlers-Danlos Syndrome/genetics
• Ehlers-Danlos Syndrome/diagnosis
• Genetic Counseling
• Genetic Diseases, Inborn/genetics
• Genetic Diseases, Inborn/diagnosis
• Genetic Testing
• Osteogenesis Imperfecta/genetics
• Osteogenesis Imperfecta/diagnosis
• Osteogenesis Imperfecta/therapy
• Preconception Care
• Pregnancy Complications/genetics
• Pregnancy Complications/therapy
• Prenatal Diagnosis/methods
• Turner Syndrome/genetics
• Turner Syndrome/diagnosis

• Humans
• Cystic Fibrosis/mortality
• Cystic Fibrosis/physiopathology
• Cystic Fibrosis/complications
• Male
• Retrospective Studies
• Female
• Adult
• Brazil/epidemiology
• Young Adult
• Forced Expiratory Volume
• Adolescent
• Spirometry
• Risk Factors
• Vital Capacity
• Respiratory Function Tests
• Age Factors

• All of Us Research Program
• Electronic Health Records
• UK Biobank
• cohort
• phenome-wide association studies
• prevalence

• Humans
• Phenomics
• Biological Specimen Banks
• UK Biobank
• Population Health
• Phenotype
• United Kingdom/epidemiology

• OT2 OD026556 NIH HHS
• U2C OD023196 NIH HHS
• OT2 OD026551 NIH HHS
• U24 OD023121 NIH HHS
• OT2 OD026552 NIH HHS
• OT2 OD026549 NIH HHS
• OT2 OD025337 NIH HHS
• OT2 OD026555 NIH HHS
• OT2 OD026550 NIH HHS
• OT2 OD026553 NIH HHS
• OT2 OD023205 NIH HHS
• OT2 OD025276 NIH HHS
• OT2 OD026557 NIH HHS
• OT2 OD026554 NIH HHS
• OT2 OD023206 NIH HHS
• U24 OD023176 NIH HHS
• OT2 OD026548 NIH HHS
• R01 LM010685 NLM NIH HHS
• OT2 OD025315 NIH HHS
• ZIA HG200417 Intramural NIH HHS
• OT2 OD025277 NIH HHS
• R01LM010685 NLM NIH HHS
• U24 OD023163 NIH HHS
• National Human Genome Research
• Intramural Research
• National Library of Medicine

• CRISPR-Cas9
• cystic fibrosis
• nanoparticles
• splice mutation
• targeted excision

• P30 DK065988 NIDDK NIH HHS

• CFTR
• CRISPR
• HITI
• W1282X
• adenine base editing

• Humans
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Gene Editing
• Codon, Nonsense/genetics
• RNA, Messenger/genetics
• RNA, Messenger/metabolism
• Mutation

• HARRIS17G0 Cystic Fibrosis Foundation
• SRC006 Cystic Fibrosis Trust
• Research Innovation award from Vertex Pharmaceuticals
• UIDB/04046/2020 Centre grants from Fundação para a Ciência e a Tecnologia, Portugal
• PD65-2012 Fundação para a Ciência e a Tecnologia

• chronic diseases
• pediatrics and adolescent medicine

• CFSPID
• CFTR variants
• Cystic fibrosis
• Variants of varying clinical consequence

• Infant, Newborn
• Male
• Humans
• Child
• Cystic Fibrosis/genetics
• Weaning
• Neonatal Screening
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Phenotype
• Mutation

• blood glucose control
• continuous glucose monitoring (cgm)
• cystic fibrosis (cf)
• cystic fibrosis related diabetes
• cystic fibrosis transmembrane conductance regulator
• cystic fibrosis triple therapy
• glycated hemoglobin (hba1c)
• ogtt

• CFTR
• Cystic fibrosis
• Genome editing
• Theratypes

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a plasma membrane protein expressed on the apical surface of secretory epithelia of the airways. In the airways, defective or absent function of the CFTR protein determines abnormalities of chloride and bicarbonate secretion and, in general, of the transepithelial homeostasis that lead to alterations of airway surface liquid (ASL) composition and properties. The reduction of ASL volume impairs ciliary beating with the consequent accumulation of a sticky mucus. This situation prevents normal mucociliary clearance, favoring the survival and proliferation of bacteria and contributing to the genesis of the CF pulmonary disease. We explored the potential of some CFTR modulators, namely ivacaftor, tezacaftor, elexacaftor and their combination Kaftrio^TM, capable of partially recovering the basic defects of the CFTR protein, to ameliorate the transepithelial fluid transport and the viscoelastic properties of the mucus when used singly or in combination. Primary human bronchial epithelial cells obtained from CF and non-CF patients were differentiated into a mucociliated epithelia in order to assess the effects of correctors tezacaftor, elexacaftor and their combination with potentiator ivacaftor on the key properties of ASL, such as fluid reabsorption, viscosity, protein content and pH. The treatment of airway epithelia bearing the deletion of a phenylalanine at position 508 (F508del) in the CFTR gene with tezacaftor and elexacaftor significantly improved the pericilial fluid composition, reducing the fluid reabsorption, correcting the ASL pH and reducing the viscosity of the mucus. Kaftrio^TM was more effective than single modulators in improving all the evaluated parameters, demonstrating once more that this combination recently approved for patients 6 years and older with cystic fibrosis who have at least one F508del mutation in the CFTR gene represents a valuable tool to defeat CF.

• Aminophenols
• Benzodioxoles/pharmacology
• Bicarbonates/metabolism
• Chlorides/metabolism
• Cystic Fibrosis/drug therapy
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Humans
• Mutation
• Phenylalanine/genetics
• Quinolones

• CFTR
• Cystic fibrosis
• Gene modules
• Gene ontology
• M-module
• Network biology
• Transcriptional profiling

• bioinformatics
• genomic variants
• newborn screening
• next-generation sequencing

• cystic fibrosis
• cftr
• genomic database
• sequence-to-structure
• eqtls
• comodifiers

• Amino Acid Substitution
• Cystic Fibrosis/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/chemistry
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Genetic Heterogeneity
• Genome-Wide Association Study
• Genomics
• Humans
• Linkage Disequilibrium
• Mutation
• Polymorphism, Single Nucleotide
• Quantitative Trait Loci
• Transcriptome

• K01 ES025435 NIEHS NIH HHS
• K01-ES025435 NIH HHS
• K01-ES025435 NIH HHS

Patient-oriented research approaches that reflect the needs and priorities of those most affected by health research outcomes improves translation of research findings into practice. Targeted therapies for cystic fibrosis (CF) are now a viable treatment option for some eligible individuals despite the heterogeneous patient-specific therapeutic response. This has necessitated development of a clinical tool that predicts treatment response for individual patients. Patient-derived mini-organs (organoids) have been at the forefront of this development. However, little is known about their acceptability in CF patients and members of the public.

We used a cross-sectional observational design to conduct an online survey in people with CF, their carers and community comparisons. Acceptability was examined in five domains: 1) willingness to use organoids, 2) perceived advantages and disadvantages of organoids, 3) acceptable out-of-pocket costs, 4) turnaround time and 5) source of tissue.

In total, 188 participants completed the questionnaire, including adults with CF and parents of children with CF (90 (48%)), and adults without CF and parents of children without CF (98 (52%)). Use of organoids to guide treatment decisions in CF was acceptable to 86 (95%) CF participants and 98 (100%) community participants. The most important advantage was that organoids may improve treatment selection, improving the patient's quality of life and life expectancy. The most important disadvantage was that the organoid recommended treatment might be unavailable or too expensive.

These findings indicate acceptance of patient-derived organoids as a tool to predict treatment response by the majority of people surveyed. This may indicate successful future implementation into healthcare systems.

The perspective regarding clinical use of patient-derived organoid models to enable cystic fibrosis personalised therapeutic decision-making of 188 participating adults surveyedhttps://bit.ly/30nWDJ7

• CFTR
• cystic fibrosis
• drug development
• proteostasis
• small molecules
• transcriptomics

• Binding Sites
• Clinical Trials as Topic
• Cystic Fibrosis/drug therapy
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/chemistry
• Cystic Fibrosis Transmembrane Conductance Regulator/drug effects
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Drug Discovery
• Endoplasmic Reticulum Stress
• High-Throughput Screening Assays
• Humans
• Ion Channel Gating/genetics
• Models, Molecular
• Molecular Chaperones/metabolism
• Mutation
• Protein Conformation
• Protein Domains
• Protein Folding
• Protein Stability
• Protein Transport
• Proteostasis/drug effects
• RNA, Messenger/biosynthesis
• RNA, Messenger/chemistry
• RNA, Messenger/genetics
• RNA, Untranslated/genetics
• Sequence Deletion
• Structure-Activity Relationship
• Transcriptome
• Ubiquitin-Protein Ligases/metabolism

• DK54759 NIH HHS
• T32GM008629 NIH HHS
• P01 HL51670 NIH HHS
• UG3 HL-147366 NIH HHS
• P30 DK054759 NIDDK NIH HHS
• R01 HL118000 NIH HHS
• P01 HL091842 NIH HHS
• T32 GM008629 NIGMS NIH HHS

• targeted gene repair
• crispr-cas9 genome editing

• Adenine/chemistry
• Alleles
• Animals
• CRISPR-Cas Systems
• Cell Line
• Codon
• Codon, Nonsense
• Cystic Fibrosis/pathology
• Gene Editing
• HEK293 Cells
• Humans
• Mice
• Mutation
• Nucleotides
• Phenotype
• Plasmids
• RNA, Guide, CRISPR-Cas Systems/chemistry
• RNA, Messenger/chemistry
• Transfection
• Uridine/analogs & derivatives
• Uridine/chemistry

• P01 HL131471 NHLBI NIH HHS
• RM1 HG009490 NHGRI NIH HHS
• P30 CA014051 NCI NIH HHS
• R35 GM118062 NIGMS NIH HHS
• U01 AI142756 NIAID NIH HHS
• R01 EB022376 NIBIB NIH HHS
• UG3 HL147367 NHLBI NIH HHS
• DP2 HL137167 NHLBI NIH HHS
• Howard Hughes Medical Institute
• American Cancer Society (American Cancer Society, Inc.)
• Cystic Fibrosis Foundation (CF Foundation)

Hepatic steatosis is a common form of cystic fibrosis associated liver disease (CFLD) seen in an estimated 15%-60% of patients with cystic fibrosis (CF). The pathophysiology and health implications of hepatic steatosis in cystic fibrosis remain largely unknown. In the general population, hepatic steatosis is strongly associated with insulin resistance and type 2 diabetes. Cystic fibrosis related diabetes (CFRD) impacts 40%-50% of CF adults and is characterized by both insulin insufficiency and insulin resistance. We hypothesized that patients with CFRD would have higher levels of hepatic steatosis than cystic fibrosis patients without diabetes.

To determine whether CFRD is associated with hepatic steatosis and to explore the impact of lumacaftor/ivacaftor therapy on hepatic steatosis in CF.

Thirty patients with CF were recruited from a tertiary care medical center for this cross-sectional study. Only pancreatic insufficient patients with CFRD or normal glucose tolerance (NGT) were included. Patients with established CFLD, end stage lung disease, or persistently elevated liver enzymes were excluded. Mean magnetic resonance imaging (MRI) proton density fat fraction (PDFF) was obtained for all participants. Clinical characteristics [age, sex, body mass index, percent predicted forced expiratory volume at 1 s (FEV1), lumacaftor/ivacaftor use] and blood chemistries were assessed for possible association with hepatic steatosis. Hepatic steatosis was defined as a mean MRI PDFF > 5%. Patients were grouped by diabetes status (CFRD, NGT) and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use (lumacaftor/ivacaftor, no lumacaftor/ivacaftor) to determine between group differences. Continuous variables were analyzed with a Wilcoxon rank sum test and discrete variables with a Chi square test or Fisher’s exact test.

Twenty subjects were included in the final analysis. The median age was 22.3 years (11.3-39.0) and median FEV1 was 77% (33%-105%). Twelve subjects had CFRD and 8 had NGT. Nine subjects were receiving lumacaftor/ivacaftor. The median PDFF was 3.0% (0.0%-21.0%). Six subjects (30%) had hepatic steatosis defined as PDFF > 5%. Hepatic fat fraction was significantly lower in patients receiving lumacaftor/ivacaftor (median, range) (2.0%, 0.0%-6.4%) than in patients not receiving lumacaftor/ivacaftor (4.1%, 2.7-21.0%), P = 0.002. Though patients with CFRD had lower PDFF (2.2%, 0.0%-14.5%) than patients with NGT (4.9%, 2.4-21.0%) this did not reach statistical significance, P = 0.06. No other clinical characteristic was strongly associated with hepatic steatosis.

Use of the CFTR modulator lumacaftor/ivacaftor was associated with significantly lower hepatic steatosis. No association between CFRD and hepatic steatosis was found in this cohort.

• Cystic fibrosis
• Liver disease
• Non-alcoholic fatty liver disease
• Cystic fibrosis transmembrane conductance regulator
• Lumacaftor/ivacaftor
• Cystic fibrosis transmembrane conductance regulator modulator
• Diabetes mellitus

As the use of next-generation sequencing (NGS) for the Mendelian diseases diagnosis is expanding, the performance of this method has to be improved in order to achieve higher quality. Typically, performance measures are considered to be designed in the context of each application and, therefore, account for a spectrum of clinically relevant variants. We present EphaGen, a new computational methodology for bioinformatics quality control (QC). Given a single NGS dataset in BAM format and a pre-compiled VCF-file of targeted clinically relevant variants it associates this dataset with a single arbiter parameter. Intrinsically, EphaGen estimates the probability to miss any variant from the defined spectrum within a particular NGS dataset. Such performance measure virtually resembles the diagnostic sensitivity of given NGS dataset. Here we present case studies of the use of EphaGen in context of BRCA1/2 and CFTR sequencing in a series of 14 runs across 43 blood samples and 504 publically available NGS datasets. EphaGen is superior to conventional bioinformatics metrics such as coverage depth and coverage uniformity. We recommend using this software as a QC step in NGS studies in the clinical context. Availability: https://github.com/m4merg/EphaGen or https://hub.docker.com/r/m4merg/ephagen.

• AAV
• CRISPR
• Cas9
• base editing
• cystic fibrosis
• gene editing
• guideRNA
• ribonucleotide particle

• Animals
• Cystic Fibrosis/genetics
• Cystic Fibrosis/pathology
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Disease Models, Animal
• Gene Editing
• Genetic Therapy
• Humans
• Mutation

Medical society guidelines recommend offering genotyping-based cystic fibrosis (CF) carrier screening to pregnant women or women considering pregnancy. We assessed the performance of sequencing-based CF screening relative to genotyping, in terms of analytical validity, clinical validity, clinical impact, and clinical utility.

Analytical validity was assessed using orthogonal confirmation and reference samples. Clinical validity was evaluated using the CFTR2 database. Clinical impact was assessed using ~100,000 screened patients. Three screening strategies were compared: genotyping 23 guideline-recommended variants (“CF23”), sequencing all coding bases in CFTR (“NGS”), and sequencing with large copy-number variant (CNV) identification (“NGS + CNV”). Clinical utility was determined via self-reported actions of at-risk couples (ARCs).

Analytical accuracy of NGS + CNV was 100% for SNVs, indels, and CNVs; interpretive clinical specificity relative to CFTR2 was 99.5%. NGS + CNV detected 58 ARCs, 18 of whom would have gone undetected with CF23 alone. Most ARCs (89% screened preconceptionally, 56% prenatally) altered pregnancy management, and no significant differences were observed between ARCs with or without at least one non-CF23 variant.

Modern NGS and variant interpretation enable accurate sequencing-based CF screening. Limiting screening to 23 variants does not improve analytical validity, clinical validity, or clinical utility, but does fail to detect approximately 30% (18/58) of ARCs.

• carrier screening
• cystic fibrosis
• sequencing

Cystic fibrosis (CF) is a rare disease most commonly seen in Caucasians. Only a few Chinese CF patients have been described in literature, taking into account the large population of China. In this systematic review, we collected the clinical and genetic information of 71 Chinese CF patients based on all available data. Compared with Caucasians, Chinese CF patients often present atypical symptoms, mainly displaying symptoms of pulmonary infection with fewer digestive symptoms. An ethnicity-specific CFTR variant spectrum was also observed in CF patients of Chinese origin, with p.Gly970Asp as the most common mutation while p.Phe508del, the most common pathogenic mutation in CF patients of Caucasian origin, is rare, suggesting the necessity of a Chinese-specific CFTR variant screening panel. Besides, multiplex ligation-dependent probe amplification analysis should be routinely considered, especially for those with unidentified mutations. Potential under-diagnosis of CF in Chinese patients might be caused by a combination of atypical clinical features and genetic heterogeneity in Chinese CF patients, the inaccessibility of sweat and genetic testing facilities, and the one-child policy in China. With the approval of promising small molecule correctors and potentiators, molecular characterization of Chinese-specific CFTR mutations will help to realize more precise treatment for Chinese CF patients.

• CFTR
• Chinese patients
• Cystic fibrosis
• Genetics
• Phenotype

• Arab world
• cystic fibrosis
• molecular epidemiology

ABC (ATP-Binding Cassette) proteins with altered function are responsible for numerous human diseases. To aid the selection of positions and amino acids for ABC structure/function studies we have generated a database, ABCMdb (Gyimesi et al., ABCMdb: a database for the comparative analysis of protein mutations in ABC transporters, and a potential framework for a general application. Hum Mutat 2012; 33:1547–1556.), with interactive tools. The database has been populated with mentions of mutations extracted from full text papers, alignments and structural models. In the new version of the database we aimed to collect the effect of mutations from databases including ClinVar. Because of the low number of available data, even in the case of the widely studied disease-causing ABC proteins, we also included the possible effects of mutations based on SNAP2 and PROVEAN predictions. To aid the interpretation of variations in non-coding regions, the database was supplemented with related DNA level information. Our results emphasize the importance of in silico predictions because of the sparse information available on variants and suggest that mutations at analogous positions in homologous ABC proteins have a strong predictive power for the effects of mutations. Our improved ABCMdb advances the design of both experimental studies and meta-analyses in order to understand drug interactions of ABC proteins and the effects of mutations on functional expression.

Database URL:http://abcm2.hegelab.org

• Alternative Splicing
• Amino Acid Motifs
• CRISPR-Cas Systems
• Cell Separation
• Codon
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Exons
• Flow Cytometry
• Gene Deletion
• Humans
• Introns
• Mutation
• Oligonucleotides/genetics
• RNA, Guide, CRISPR-Cas Systems/genetics
• RNA, Messenger/genetics

• Cystic Fibrosis Trust (GB)
• Cystic Fibrosis Foundation Therapeutics

CFTR2 provides clinical and functional information of the most common CFTR-mutations. Rare mutations (RMs) occur in only a few patients with limited reported clinical data. Their role in CF-disease liability is hardly documented.

Belgian CF-Registry 2013 data were analyzed to identify CF with at least 1 RM (CF_+RM). Clinical data and sweat chloride of CF_+RM were compared to CF-controls, carrying 2 class 1 to 3 mutations (CF_classic). Disease severity was compared between both groups. To avoid bias in the comparison, transplanted patients were excluded from each group.

Seventy-seven CF_+RM were identified (77/1183 = 6.5%). Sixty-four different RM were detected, of which 21 had not been previously reported. All RMs, corresponding to HGVS (Human Genome Variation Society) nomenclature, were listed in supplementary data.

Seven transplanted CF_+RM were excluded for further analysis. CF_+RM had higher age at diagnosis [median (IQR)] [3.7 y (0.3–18.3) vs. 0.3y (0.1–2,0) (p < 0.0001)], lower sweat chloride [96 mmol/L (64–107) vs. 104 mmol/L (97–115) (p < 0.0001)], higher FEV₁%pred [77%pred (58–96) vs. 68%pred (48–86) (p = 0.017)], were less frequently pancreatic insufficient [56% vs. 98% (p < 0.0001)], Pseudomonas aeruginosa colonized [24% vs. 44% (p = 0.0093)] and needed fewer IV antibiotics [36% vs. 51% (p = 0.041)] than CF_classic. However, a wide spectrum of disease severity was seen amongst CF_+RM.

CF-patients with a RM cover 6.5% of the Belgian CF-population. Rare mutations can be found in severely ill patients, but more often in late diagnosed, pancreatic sufficient patients.

The online version of this article (doi:10.1186/s13023-017-0694-1) contains supplementary material, which is available to authorized users.

• CF-registry study
• Cystic fibrosis
• Disease liability
• Genotype-phenotype correlation
• Rare CFTR-mutations

• biomarker
• heritability
• ivacaftor
• lumacaftor
• pilocarpine iontophoresis

• Adult
• Biomarkers/metabolism
• Chlorides/metabolism
• Cystic Fibrosis/metabolism
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• Female
• Humans
• Male
• Sweat/metabolism
• Young Adult

• MOP-258915 CIHR
• R01 HL128475 NHLBI NIH HHS
• R01 HL068927 NHLBI NIH HHS
• R01 HL068890 NHLBI NIH HHS
• R01 DK044003 NIDDK NIH HHS

• cystic fibrosis
• epidemiology
• genetics
• newborn screening

• CRISPR-Cas Systems
• Cell Line
• Cystic Fibrosis/genetics
• Cystic Fibrosis/metabolism
• Cystic Fibrosis/pathology
• Cystic Fibrosis Transmembrane Conductance Regulator/genetics
• Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
• DNA Breaks, Double-Stranded
• DNA Repair
• Epithelial Cells/metabolism
• Epithelial Cells/pathology
• Humans
• RNA, Guide, CRISPR-Cas Systems/genetics
• RNA, Guide, CRISPR-Cas Systems/metabolism

ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) at the National Center for Biotechnology Information (NCBI) is a freely available archive for interpretations of clinical significance of variants for reported conditions. The database includes germline and somatic variants of any size, type or genomic location. Interpretations are submitted by clinical testing laboratories, research laboratories, locus-specific databases, OMIM®, GeneReviews™, UniProt, expert panels and practice guidelines. In NCBI's Variation submission portal, submitters upload batch submissions or use the Submission Wizard for single submissions. Each submitted interpretation is assigned an accession number prefixed with SCV. ClinVar staff review validation reports with data types such as HGVS (Human Genome Variation Society) expressions; however, clinical significance is reported directly from submitters. Interpretations are aggregated by variant-condition combination and assigned an accession number prefixed with RCV. Clinical significance is calculated for the aggregate record, indicating consensus or conflict in the submitted interpretations. ClinVar uses data standards, such as HGVS nomenclature for variants and MedGen identifiers for conditions. The data are available on the web as variant-specific views; the entire data set can be downloaded via ftp. Programmatic access for ClinVar records is available through NCBI's E-utilities. Future development includes providing a variant-centric XML archive and a web page for details of SCV submissions.

Ivacaftor acts as a potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) and increases the transepithelial chloride transport of CFTR in 9 of 10 known gating mutations causing cystic fibrosis. S549R is a rare gating mutation considered to be less sensitive to potentiators than all other gating mutations.

We report our first experience with ivacaftor in an 8-year-old boy with the rare S549R gating mutation. Besides subjective clinical improvements, the sweat chloride level and the lung clearance index decreased impressively within a few weeks of treatment while forced expiratory volume in the first second values remained in normal range.

We emphasize the value of measuring small airway function by lung clearance index as an outcome measure for new interventions targeting the correction of the CFTR defect at an age before traditional lung function parameters start to deteriorate.

• epithelium
• genes
• genetics

Cystic fibrosis is the most common autosomal recessive genetic disease in Caucasians and has been extensively studied for many decades. The cystic fibrosis transmembrane conductance regulator gene was identified in 1989. It encodes a complex protein which has numerous cellular functions. Our understanding of cystic fibrosis pathophysiology and genetics is constantly expanding and being refined, leading to improved management of the disease and increased life expectancy in affected individuals.

• ACOG panel
• CFTR gene
• MiSeq
• Next-Generation sequencing
• carrier screening