scholarly journals Short structural variants as informative genetic markers for ALS disease risk and progression

BMC Medicine ◽  
2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Frances Theunissen ◽  
Loren L. Flynn ◽  
Ryan S. Anderton ◽  
P. Anthony Akkari

AbstractThere is considerable variability in disease progression for patients with amyotrophic lateral sclerosis (ALS) including the age of disease onset, site of disease onset, and survival time. There is growing evidence that short structural variations (SSVs) residing in frequently overlooked genomic regions can contribute to complex disease mechanisms and can explain, in part, the phenotypic variability in ALS patients. Here, we discuss SSVs recently characterized by our laboratory and how these discoveries integrate into the current literature on ALS, particularly in the context of application to future clinical trials. These markers may help to identify and differentiate patients for clinical trials that have a similar ALS disease mechanism(s), thereby reducing the impact of participant heterogeneity. As evidence accumulates for the genetic markers discovered in SQSTM1, SCAF4, and STMN2, we hope to improve the outcomes of future ALS clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11508-11508
Author(s):  
Dawn L. Hershman ◽  
Cathee Till ◽  
Jason Dennis Wright ◽  
Melissa Kate Accordino ◽  
Riha Vaidya ◽  
...  

11508 Background: Cardiovascular-disease risk factors (CVD-RFs) increase the risk of cardiac events in women undergoing chemotherapy. Less is known about the impact of CVD-RFs on healthcare utilization and costs. Methods: We examined breast cancer patients treated uniformly on SWOG clinical trials from 1999-2011. We identified baseline diabetes, hypertension, hypercholesterolemia, and coronary artery disease (CAD) by linking trial records to Medicare claims; obesity was identified using clinical records. The outcomes were emergency room visits (ER), hospitalizations and costs. Multivariable logistic and linear regression were used. Results: Among the 708 patients included in the analysis, 160 (22.6%) experienced 234 separate hospitalizations, and 193 (27.3%) experienced 311 separate ER visits. Diabetes, hypertension, hypercholesterolemia, and CAD were all associated with increased risk of hospitalizations and ER visit. Hypertension had the strongest association, with more than a threefold risk of hospitalization for those with hypertension compared to those without (OR [95% CI], 3.16 [1.85-5.40], p<0.001). For those with ≥3 CVD-RFs, the risk of hospitalization was greater compared to 0 or 1 CVD-RFs (OR [95% CI], 2.74 [1.71-4.38], p<0.001). Similar results were seen for ER visits. In the first 12 months after trial registration, patients with diabetes ($38,324 vs $30,923, 23.9% increase, p=0.05), hypercholesterolemia ($34,168 vs $30,661, 11.4% increase, p=0.02), and CAD ($37,781 vs $31,698, 19.2% increase, p=0.04) had statistically significantly higher total healthcare costs. Additionally, those with 2 significant CVD-RFs ($35,353 vs. $28,899, 22.3% increase, p=.005) had higher total healthcare costs. Conclusions: Our study demonstrates that the presence of both CVD-RFs and ER visits and hospitalizations are frequent among elderly BC patients. The risk of ER visits and hospitalizations is higher among patients with CVD-RFs, and increases with the number of RFs. Better management of CVD-RFs and more aggressive symptom management may be required to reduce both physical and financial toxicities to elderly patients undergoing BC therapy.


eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Todd Lencz ◽  
Daniel Backenroth ◽  
Einat Granot-Hershkovitz ◽  
Adam Green ◽  
Kyle Gettler ◽  
...  

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. Here we predict, based on the liability threshold model, the expected reduction in complex disease risk following polygenic embryo screening for a single disease. A strong determinant of the potential utility of such screening is the selection strategy, a factor that has not been previously studied. When only embryos with a very high PRS are excluded, the achieved risk reduction is minimal. In contrast, selecting the embryo with the lowest PRS can lead to substantial relative risk reductions, given a sufficient number of viable embryos. We systematically examine the impact of several factors on the utility of screening, including: variance explained by the PRS, number of embryos, disease prevalence, parental PRSs, and parental disease status. We consider both relative and absolute risk reductions, as well as population-averaged and per-couple risk reductions, and also examine the risk of pleiotropic effects. Finally, we confirm our theoretical predictions by simulating ‘virtual’ couples and offspring based on real genomes from schizophrenia and Crohn’s disease case-control studies. We discuss the assumptions and limitations of our model, as well as the potential emerging ethical concerns.


2014 ◽  
Vol 2 (1) ◽  
pp. 114
Author(s):  
John Rizzo ◽  
David Lee

This paper develops a conceptual model for understanding the impact of the “value of knowing”, defined as the value of information from medical tests exclusive of treatment or life-planning decisions on a patient’s decision to undergo testing.  We draw upon the behavioral economic, loss-aversion, cost-benefit and willingness-to-pay literatures to develop a mathematical model of how a medical diagnostic test affects patients’ sense of wellbeing and how this phenomenon affects their decision to undergo testing.  The model allows simultaneous evaluation of the impact of baseline (pre-test) disease risk, test inaccuracy, prior information, worrying over disease onset, time preference and the degree of loss aversion on patients’ net assessment of the value of knowing.  We then simulate the net value of knowing under alternative hypothetical scenarios about test accuracy and patient characteristics.              Patients agree to testing when the expected benefits from good news (measured by willingness to pay) exceed the psychic costs of bad news (measured by willingness to accept).  The value of knowing from testing is shown to depend on test accuracy, pre-test disease risk, the patient’s discount rate, time to disease onset and the patient’s aversion to receiving bad news (loss).  Simulation results indicate that the value of knowing increases (and testing becomes more likely) when: tests are more accurate; the baseline expectation of a positive test is low and the adverse consequences of a positive test are either small or occur far in the future or patients do not worry about onset of future disease.


2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Franziska Witte ◽  
Jorge Ruiz-Orera ◽  
Camilla Ciolli Mattioli ◽  
Susanne Blachut ◽  
Eleonora Adami ◽  
...  

Abstract Background Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.


2015 ◽  
Vol 54 (03) ◽  
pp. 94-100 ◽  
Author(s):  
P. B. Musholt ◽  
T. J. Musholt

SummaryAim: Thyroid nodules > 1 cm are observed in about 12% of unselected adult employees aged 18–65 years screened by ultrasound scan (40). While intensive ultrasound screening leads to early detection of thyroid diseases, the determination of benign or malignant behaviour remains uncertain and may trigger anxieties in many patients and their physicians. A considerable number of thyroid resections are consecutively performed due to suspicion of malignancy in the detected nodes. Fine needle aspiration biopsy (FNAB) has been recommended for the assessment of thyroid nodules to facilitate detection of thyroid carcinomas but also to rule out malignancy and thereby avoid unnecessary thyroid resections. However, cytology results are dependent on experience of the respective cytologist and unfortunately inconclusive in many cases. Methods: Molecular genetic markers are already used nowadays to enhance sensitivity and specificity of FNAB cytology in some centers in Germany. The most clinically relevant molecular genetic markers as pre-operative diagnostic tools and the clinical implications for the intraoperative and postoperative management were reviewed. Results: Molecular genetic markers predominantly focus on the preoperative detection of thyroid malignancies rather than the exclusion of thyroid carcinomas. While some centers routinely assess FNABs, other centers concentrate on FNABs with cytology results of follicular neoplasia or suspicion of thyroid carcinoma. Predominantly mutations of BRAF, RET/PTC, RAS, and PAX8/PPARγ or expression of miRNAs are analyzed. However, only the detection of BRAF mutations predicts the presence of (papillary) thyroid malignancy with almost 98% probability, indicating necessity of oncologic thyroid resections irrespective of the cytology result. Other genetic alterations are associated with thyroid malignancy with varying frequency and achieve less impact on the clinical management. Conclusion: Molecular genetic analysis of FNABs is increasingly performed in Germany. Standardization, quality controls, and validation of various methods need to be implemented in the near future to be able to compare the results. With increasing knowledge about the impact of genetic alterations on the prognosis of thyroid carcinomas, recommendations have to be defined that may lead to individually optimized treatment strategies.


2021 ◽  
Vol 7 (3) ◽  
pp. 47
Author(s):  
Marios Lange ◽  
Rodiola Begolli ◽  
Antonis Giakountis

The cancer genome is characterized by extensive variability, in the form of Single Nucleotide Polymorphisms (SNPs) or structural variations such as Copy Number Alterations (CNAs) across wider genomic areas. At the molecular level, most SNPs and/or CNAs reside in non-coding sequences, ultimately affecting the regulation of oncogenes and/or tumor-suppressors in a cancer-specific manner. Notably, inherited non-coding variants can predispose for cancer decades prior to disease onset. Furthermore, accumulation of additional non-coding driver mutations during progression of the disease, gives rise to genomic instability, acting as the driving force of neoplastic development and malignant evolution. Therefore, detection and characterization of such mutations can improve risk assessment for healthy carriers and expand the diagnostic and therapeutic toolbox for the patient. This review focuses on functional variants that reside in transcribed or not transcribed non-coding regions of the cancer genome and presents a collection of appropriate state-of-the-art methodologies to study them.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Zhenyang Liao ◽  
Xunxiao Zhang ◽  
Shengcheng Zhang ◽  
Zhicong Lin ◽  
Xingtan Zhang ◽  
...  

Abstract Background Structural variations (SVs) are a type of mutations that have not been widely detected in plant genomes and studies in animals have shown their role in the process of domestication. An in-depth study of SVs will help us to further understand the impact of SVs on the phenotype and environmental adaptability during papaya domestication and provide genomic resources for the development of molecular markers. Results We detected a total of 8083 SVs, including 5260 deletions, 552 tandem duplications and 2271 insertions with deletion being the predominant, indicating the universality of deletion in the evolution of papaya genome. The distribution of these SVs is non-random in each chromosome. A total of 1794 genes overlaps with SV, of which 1350 genes are expressed in at least one tissue. The weighted correlation network analysis (WGCNA) of these expressed genes reveals co-expression relationship between SVs-genes and different tissues, and functional enrichment analysis shows their role in biological growth and environmental responses. We also identified some domesticated SVs genes related to environmental adaptability, sexual reproduction, and important agronomic traits during the domestication of papaya. Analysis of artificially selected copy number variant genes (CNV-genes) also revealed genes associated with plant growth and environmental stress. Conclusions SVs played an indispensable role in the process of papaya domestication, especially in the reproduction traits of hermaphrodite plants. The detection of genome-wide SVs and CNV-genes between cultivated gynodioecious populations and wild dioecious populations provides a reference for further understanding of the evolution process from male to hermaphrodite in papaya.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Katy Tobin ◽  
Sinead Maguire ◽  
Bernie Corr ◽  
Charles Normand ◽  
Orla Hardiman ◽  
...  

Abstract Background Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative condition with a mean life expectancy of 3 years from first symptom. Understanding the factors that are important to both patients and their caregivers has the potential to enhance service delivery and engagement, and improve efficiency. The Discrete Choice Experiment (DCE) is a stated preferences method which asks service users to make trade-offs for various attributes of health services. This method is used to quantify preferences and shows the relative importance of the attributes in the experiment, to the service user. Methods A DCE with nine choice sets was developed to measure the preferences for health services of ALS patients and their caregivers and the relative importance of various aspects of care, such as timing of care, availability of services, and decision making. The DCE was presented to patients with ALS, and their caregivers, recruited from a national multidisciplinary clinic. A random effects probit model was applied to estimate the impact of each attribute on a participant’s choice. Results Patients demonstrated the strongest preferences about timing of receiving information about ALS. A strong preference was also placed on seeing the hospice care team later rather than early on in the illness. Patients also indicated their willingness to consider the use of communication devices. Grouping by stage of disease, patients who were in earlier stages of disease showed a strong preference for receipt of extensive information about ALS at the time of diagnosis. Caregivers showed a strong preference for engagement with healthcare professionals, an attribute that was not prioritised by patients. Conclusions The DCE method can be useful in uncovering priorities of patients and caregivers with ALS. Patients and caregivers have different priorities relating to health services and the provision of care in ALS, and patient preferences differ based on the stage and duration of their illness. Multidisciplinary teams must calibrate the delivery of care in the context of the differing expectations, needs and priorities of the patient/caregiver dyad.


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