Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine

Butnariu, Lăcrămioara Ionela; Ţarcă, Elena; Cojocaru, Elena; Rusu, Cristina; Moisă, Ştefana Maria; Leon‐Constantin, Maria‐Magdalena; Gorduza, Eusebiu Vlad; Trandafir, Laura Mihaela

doi:10.3390/jcm10245821

Cited by 24 publications

(18 citation statements)

References 129 publications

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“…For example, in a truly polygenic disease (i.e., a genetic disorder resulting from the combined action of two or more genes, the implicated genes may in principle be termed disease-predisposing genes and all pathologically relevant variants within these genes may accordingly be classified as “disease-predisposing”. Moreover, in classical autosomal dominant diseases (e.g., autosomal dominant polycystic kidney disease (ADPKD) [ 70 ]) or autosomal recessive diseases (e.g., cystic fibrosis [ 71 ]), the so-called modifier genes may in principle be termed disease-predisposing genes. Further, the so-called hypomorphic alleles in some disease-causing genes may be classified as “predisposing” (e.g., [ 72 ]).…”

Section: Discussionmentioning

confidence: 99%

Expanding ACMG variant classification guidelines into a general framework

et al. 2022

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Background The American College of Medical Genetics and Genomics (ACMG)-recommended five variant classification categories (pathogenic, likely pathogenic, uncertain significance, likely benign, and benign) have been widely used in medical genetics. However, these guidelines are fundamentally constrained in practice owing to their focus upon Mendelian disease genes and their dichotomous classification of variants as being either causal or not. Herein, we attempt to expand the ACMG guidelines into a general variant classification framework that takes into account not only the continuum of clinical phenotypes, but also the continuum of the variants’ genetic effects, and the different pathological roles of the implicated genes. Main body As a disease model, we employed chronic pancreatitis (CP), which manifests clinically as a spectrum from monogenic to multifactorial. Bearing in mind that any general conceptual proposal should be based upon sound data, we focused our analysis on the four most extensively studied CP genes, PRSS1, CFTR, SPINK1 and CTRC. Based upon several cross-gene and cross-variant comparisons, we first assigned the different genes to two distinct categories in terms of disease causation: CP-causing (PRSS1 and SPINK1) and CP-predisposing (CFTR and CTRC). We then employed two new classificatory categories, “predisposing” and “likely predisposing”, to replace ACMG’s “pathogenic” and “likely pathogenic” categories in the context of CP-predisposing genes, thereby classifying all pathologically relevant variants in these genes as “predisposing”. In the case of CP-causing genes, the two new classificatory categories served to extend the five ACMG categories whilst two thresholds (allele frequency and functional) were introduced to discriminate “pathogenic” from “predisposing” variants. Conclusion Employing CP as a disease model, we expand ACMG guidelines into a five-category classification system (predisposing, likely predisposing, uncertain significance, likely benign, and benign) and a seven-category classification system (pathogenic, likely pathogenic, predisposing, likely predisposing, uncertain significance, likely benign, and benign) in the context of disease-predisposing and disease-causing genes, respectively. Taken together, the two systems constitute a general variant classification framework that, in principle, should span the entire spectrum of variants in any disease-related gene. The maximal compliance of our five-category and seven-category classification systems with the ACMG guidelines ought to facilitate their practical application.

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Section: Discussionmentioning

confidence: 99%

Expanding ACMG variant classification guidelines into a general framework

et al. 2022

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“…CF is caused by mutations in the CF transmembrane conductance regulator ( CFTR ) gene. This mutation leads to the buildup of mucous in many organs, especially the lungs [ 85 ]. MRT5005 encodes for CFTR and can be delivered through nebulization.…”

Section: Rna Therapeuticsmentioning

confidence: 99%

Current Advances in RNA Therapeutics for Human Diseases

Zogg

Singh

2022

IJMS

102

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Following the discovery of nucleic acids by Friedrich Miescher in 1868, DNA and RNA were recognized as the genetic code containing the necessary information for proper cell functioning. In the years following these discoveries, vast knowledge of the seemingly endless roles of RNA have become better understood. Additionally, many new types of RNAs were discovered that seemed to have no coding properties (non-coding RNAs), such as microRNAs (miRNAs). The discovery of these new RNAs created a new avenue for treating various human diseases. However, RNA is relatively unstable and is degraded fairly rapidly once administered; this has led to the development of novel delivery mechanisms, such as nanoparticles to increase stability as well as to prevent off-target effects of these molecules. Current advances in RNA-based therapies have substantial promise in treating and preventing many human diseases and disorders through fixing the pathology instead of merely treating the symptomology similarly to traditional therapeutics. Although many RNA therapeutics have made it to clinical trials, only a few have been FDA approved thus far. Additionally, the results of clinical trials for RNA therapeutics have been ambivalent to date, with some studies demonstrating potent efficacy, whereas others have limited effectiveness and/or toxicity. Momentum is building in the clinic for RNA therapeutics; future clinical care of human diseases will likely comprise promising RNA therapeutics. This review focuses on the current advances of RNA therapeutics and addresses current challenges with their development.

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“…The gut microbiome, to a lesser extent, is inherited, and to a greater extent, it is influenced by environmental factors [ 66 , 69 , 70 , 71 , 72 ].…”

Section: Impact Of Altered Gut Microbiota In Cystic Fibrosismentioning

confidence: 99%

“…Altered microbiota and local inflammation influence a child’s growth and quality of life and have an important role in gastrointestinal complications, such as malignancy. Data suggest that dysbiosis induces systemic inflammation and immune disorders that can lead to pulmonary exacerbations through the gut–lung axis [ 66 , 69 , 71 , 73 ].…”

Section: Impact Of Altered Gut Microbiota In Cystic Fibrosismentioning

confidence: 99%

Can Bioactive Food Substances Contribute to Cystic Fibrosis-Related Cardiovascular Disease Prevention?

Trandafir

Frăsinariu²,

Ţarcă³

et al. 2023

Nutrients

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Advances in cystic fibrosis (CF) care have significantly improved the quality of life and life expectancy of patients. Nutritional therapy based on a high-calorie, high-fat diet, antibiotics, as well as new therapies focused on CFTR modulators change the natural course of the disease. They do so by improving pulmonary function and growing BMI. However, the increased weight of such patients can lead to unwanted long-term cardiovascular effects. People with CF (pwCF) experience several cardiovascular risk factors. Such factors include a high-fat diet and increased dietary intake, altered lipid metabolism, a decrease in the level of fat-soluble antioxidants, heightened systemic inflammation, therapeutic interventions, and diabetes mellitus. PwCF must pay special attention to food and eating habits in order to maintain a nutritional status that is as close as possible to the proper physiological one. They also have to benefit from appropriate nutritional counseling, which is essential in the evolution and prognosis of the disease. Growing evidence collected in the last years shows that many bioactive food components, such as phytochemicals, polyunsaturated fatty acids, and antioxidants have favorable effects in the management of CF. An important positive effect is cardiovascular prevention. The possibility of preventing/reducing cardiovascular risk in CF patients enhances both quality of life and life expectancy in the long run.

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Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine

Cited by 24 publications

References 129 publications

Expanding ACMG variant classification guidelines into a general framework

Expanding ACMG variant classification guidelines into a general framework

Current Advances in RNA Therapeutics for Human Diseases

Can Bioactive Food Substances Contribute to Cystic Fibrosis-Related Cardiovascular Disease Prevention?

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