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Cystic fibrosis genetics: from molecular understanding to clinical application

This article has been updated

Key Points

  • Investigation of disease-causing variants such as F508del is resolving the mechanisms underlying cystic fibrosis transmembrane conductance regulator (CFTR) folding and will inform rational design of compounds to correct the folding of mutant CFTR.

  • New tissue culture methods will facilitate the evaluation of molecular targeted therapy for a wide array of CFTR genotypes, and new animal models should enable assessment of treatment at the earliest stages of the disease.

  • Analyses of affected twin and sibling pairs have quantified the contribution of genetic and non-genetic modifiers to variation in key features of cystic fibrosis.

  • Candidate and genome-wide approaches have identified biologically plausible gene modifiers of lung disease severity, neonatal intestinal obstruction and diabetes in cystic fibrosis.

  • Annotation of variants in CFTR will increase the utility of genetic testing in newborn screening, carrier testing and diagnostic settings. Assignment of variants as disease-causing will validate efforts to target variants for molecular therapies.

  • Small-molecule therapy for cystic fibrosis has been successful for patients carrying a subset of CFTR variants. Grouping of variants according to responses in cell-based assays (that is, theratypes) could expedite treatment of affected individuals with rare CFTR genotypes.

Abstract

The availability of the human genome sequence and tools for interrogating individual genomes provide an unprecedented opportunity to apply genetics to medicine. Mendelian conditions, which are caused by dysfunction of a single gene, offer powerful examples that illustrate how genetics can provide insights into disease. Cystic fibrosis, one of the more common lethal autosomal recessive Mendelian disorders, is presented here as an example. Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.

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Figure 1: Cardinal features of cystic fibrosis and relative contribution of genetic modifiers to variation in select cystic fibrosis traits.
Figure 2: Molecular consequences of variants in CFTR.
Figure 3: Molecular treatments for cystic fibrosis.

Change history

  • 20 November 2014

    A typographical error has been corrected in Figure 2.

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Acknowledgements

The author thanks P. Thomas, D. Sheppard, M. Knowles, M. Drumm and B. Guggino for providing commentary and critique of this Review, and members of the CFTR2 team (C. Penland, J. Rommens, C. Castellani and M. Corey) for many insights regarding the clinical and functional consequences of CFTR variants. He also thanks P. Durie, H. Corvol and the members of the International Cystic Fibrosis Modifier Consortium for discussions about modifiers of cystic fibrosis, and members of the Cutting laboratory, especially P. Sosnay, S. Blackman, J. M. Collaco and K. Raraigh, for contributions to concepts presented in this Review. The author's work is supported by grants 5R01DK044003 from the NIDDK, and grants CUTTING08A, CUTTING09A and CUTTING10A from the US Cystic Fibrosis Foundation.

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Correspondence to Garry R. Cutting.

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The author declares associations with the following organizations or companies: (consultant) aTyr Pharma, Canon Biosciences, Cystic Fibrosis Foundation, Illumina, Vertex Pharmaceuticals; (honoraria) Wiley.

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Glossary

Pancreatic exocrine

Pertaining to the portion of the pancreas that produces digestive enzymes that are combined with alkaline secretions from the pancreatic ducts and secreted into the intestine to aid digestion.

Locus-specific databases

Collections of DNA variants that have been reported in disease-associated genes.

CRISPR–Cas9 editing

A method that uses an RNA guide and a DNA-binding protein to cleave DNA at a specific location to create sequence-specific changes via homologous recombination with a donor template.

Intestinal organoids

Epithelial 'mini-guts' grown in vitro from biopsies of the rectal mucosa or from stem cells from a single individual.

Airway submucosal glands

Mucus-secreting glands found in the connective tissue that provide fluid for hydrating the surface of the airway epithelial cells and enabling ciliary function.

Airway surface liquid

Fluid interface between the air and the cells in the lungs that confers protection from infection and facilitates removal of foreign particles.

Tracheal rings

Incomplete rings of highly elastic cartilage found in the anterior two-thirds of the tracheal wall.

Endocrine pancreas

Portion of the pancreas that produces hormones (insulin and glucagon) that are essential for glucose homeostasis.

Pseudomonas aeruginosa

Widely distributed gram-negative bacteria that show a predilection for acute and chronic infection of the lungs of individuals with cystic fibrosis.

Meconium ileus

Obstruction of the gut that usually develops in utero in the ileum of the small intestine and that is highly suggestive of cystic fibrosis.

Airway flow measurements

Series of standardized tests assessing the rate and volume of air that can be inhaled and exhaled; they are used to determine the degree of disease in the lungs in individuals with cystic fibrosis.

Vas deferens

A tubular structure that conveys sperm from the testis to the urethra of the penis.

Disseminated bronchiectasis

Permanent dilation of the airways (bronchi) throughout the lungs.

Phase III clinical trials

The third of four phases of evaluating a drug in affected subjects that confirms its safety and efficacy.

Nasal potential difference

Measurement of voltage across nasal epithelia that represents the transport of ions and that, under specific conditions, can assess the function of cystic fibrosis transmembrane conductance regulator (CFTR) in vivo.

Open probability

A measure of the average fraction of time that a channel is open.

Phase II clinical trial

The second of four phases of evaluating a drug in affected subjects that establishes the efficacy of a drug compared to a placebo.

Theratypes

A recently invented term used to classify disease-associated DNA variants according to the molecular-based treatment to which they respond.

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Cutting, G. Cystic fibrosis genetics: from molecular understanding to clinical application. Nat Rev Genet 16, 45–56 (2015). https://doi.org/10.1038/nrg3849

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