Journal of Personalized Medicine

Research

19 pages, 1670 KiB

Open AccessArticle

Utilization of Targeted RNA-Seq for the Resolution of Variant Pathogenicity and Enhancement of Diagnostic Yield in Dysferlinopathy

by Laura Rufibach, Kiera Berger, Samya Chakravorty, Sarah Emmons, Laurie Long, Greg Gibson and Madhuri Hegde

J. Pers. Med. 2023, 13(3), 520; https://doi.org/10.3390/jpm13030520 - 13 Mar 2023

Viewed by 2153

Abstract

For inherited diseases, obtaining a definitive diagnosis is critical for proper disease management, family planning, and participation in clinical trials. This can be challenging for dysferlinopathy due to the significant clinical overlap between the 30+ subtypes of limb–girdle muscular dystrophy (LGMD) and the [...] Read more.

For inherited diseases, obtaining a definitive diagnosis is critical for proper disease management, family planning, and participation in clinical trials. This can be challenging for dysferlinopathy due to the significant clinical overlap between the 30+ subtypes of limb–girdle muscular dystrophy (LGMD) and the large number of variants of unknown significance (VUSs) that are identified in the dysferlin gene, DYSF. We performed targeted RNA-Seq using a custom gene-panel in 77 individuals with a clinical/genetic suspicion of dysferlinopathy and evaluated all 111 identified DYSF variants according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines. This evaluation identified 11 novel DYSF variants and allowed for the classification of 87 DYSF variants as pathogenic/likely pathogenic, 8 likely benign, while 16 variants remained VUSs. By the end of the study, 60 of the 77 cases had a definitive diagnosis of dysferlinopathy, which was a 47% increase in diagnostic yield over the rate at study onset. This data shows the ability of RNA-Seq to assist in variant pathogenicity classification and diagnosis of dysferlinopathy and is, therefore, a type of analysis that should be considered when DNA-based genetic analysis is not sufficient to provide a definitive diagnosis. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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21 pages, 3427 KiB

Open AccessArticle

Theory and Applications of the (Cardio) Genomic Fabric Approach to Post-Ischemic and Hypoxia-Induced Heart Failure

by Dumitru Andrei Iacobas and Lei Xi

J. Pers. Med. 2022, 12(8), 1246; https://doi.org/10.3390/jpm12081246 - 29 Jul 2022

Cited by 5 | Viewed by 1661

Abstract

The genomic fabric paradigm (GFP) characterizes the transcriptome topology by the transcripts’ abundances, the variability of the expression profile, and the inter-coordination of gene expressions in each pathophysiological condition. The expression variability analysis provides an indirect estimate of the cell capability to limit [...] Read more.

The genomic fabric paradigm (GFP) characterizes the transcriptome topology by the transcripts’ abundances, the variability of the expression profile, and the inter-coordination of gene expressions in each pathophysiological condition. The expression variability analysis provides an indirect estimate of the cell capability to limit the stochastic fluctuations of the expression levels of key genes, while the expression coordination analysis determines the gene networks in functional pathways. This report illustrates the theoretical bases and the mathematical framework of the GFP with applications to our microarray data from mouse models of post ischemic, and constant and intermittent hypoxia-induced heart failures. GFP analyses revealed the myocardium priorities in keeping the expression of key genes within narrow intervals, determined the statistically significant gene interlinkages, and identified the gene master regulators in the mouse heart left ventricle under normal and ischemic conditions. We quantified the expression regulation, alteration of the expression control, and remodeling of the gene networks caused by the oxygen deprivation and determined the efficacy of the bone marrow mono-nuclear stem cell injections to restore the normal transcriptome. Through the comprehensive assessment of the transcriptome, GFP would pave the way towards the development of personalized gene therapy of cardiac diseases. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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9 pages, 1312 KiB

Open AccessCommunication

WARE: Wet AMD Risk-Evaluation Tool as a Clinical Decision-Support System Integrating Genetic and Non-Genetic Factors

by Carlo Fabrizio, Andrea Termine, Valerio Caputo, Domenica Megalizzi, Stefania Zampatti, Benedetto Falsini, Andrea Cusumano, Chiara Maria Eandi, Federico Ricci, Emiliano Giardina, Claudia Strafella and Raffaella Cascella

J. Pers. Med. 2022, 12(7), 1034; https://doi.org/10.3390/jpm12071034 - 24 Jun 2022

Cited by 2 | Viewed by 1543

Abstract

Given the multifactorial features characterizing age-related macular degeneration (AMD), the availability of a tool able to provide the individual risk profile is extremely helpful for personalizing the follow-up and treatment protocols of patients. To this purpose, we developed an open-source computational tool named [...] Read more.

Given the multifactorial features characterizing age-related macular degeneration (AMD), the availability of a tool able to provide the individual risk profile is extremely helpful for personalizing the follow-up and treatment protocols of patients. To this purpose, we developed an open-source computational tool named WARE (Wet AMD Risk Evaluation), able to assess the individual risk profile for wet AMD based on genetic and non-genetic factors. In particular, the tool uses genetic risk measures normalized for their relative frequencies in the general population and disease prevalence. WARE is characterized by a user-friendly web page interface that is intended to assist clinicians in reporting risk assessment upon patient evaluation. When using the tool, plots of population risk distribution highlight a “low-risk zone” and a “high-risk zone” into which subjects can fall depending on their risk-assessment result. WARE represents a reliable population-specific computational system for wet AMD risk evaluation that can be exploited to promote preventive actions and personalized medicine approach for affected patients or at-risk individuals. This tool can be suitable to compute the disease risk adjusted to different populations considering their specific genetic factors and related frequencies, non-genetic factors, and the disease prevalence. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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19 pages, 2003 KiB

Open AccessArticle

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

by Kiera Berger, Dalia Arafat, Shanmuganathan Chandrakasan, Scott B. Snapper and Greg Gibson

J. Pers. Med. 2022, 12(6), 919; https://doi.org/10.3390/jpm12060919 - 1 Jun 2022

Cited by 1 | Viewed by 2366

Abstract

Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if [...] Read more.

Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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8 pages, 1952 KiB

Open AccessArticle

From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene

by Ioanna Pyromali, Nesrine Benslimane, Frédéric Favreau, Cyril Goizet, Leila Lazaro, Martine Vitry, Paco Derouault, Franck Sturtz, Corinne Magdelaine and Anne-Sophie Lia

J. Pers. Med. 2022, 12(2), 212; https://doi.org/10.3390/jpm12020212 - 3 Feb 2022

Cited by 4 | Viewed by 1872

Abstract

Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. [...] Read more.

Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot–Marie–Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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Review

Jump to: Research, Other

12 pages, 293 KiB

Open AccessReview

Combined Assay of rDNA and SatIII Copy Numbers as an Individual Profile of Stress Resistance, Longevity, Fertility and Disease Predisposition

by Lev N. Porokhovnik

J. Pers. Med. 2022, 12(10), 1752; https://doi.org/10.3390/jpm12101752 - 21 Oct 2022

Viewed by 1276

Abstract

The ribosomal DNA and pericentromeric satellite repeats are two important types of moderately repeated sequences existing in the human genome. They are functionally involved in the universal stress response. There is accumulating evidence that the copy number variation (CNV) of the repeat units [...] Read more.

The ribosomal DNA and pericentromeric satellite repeats are two important types of moderately repeated sequences existing in the human genome. They are functionally involved in the universal stress response. There is accumulating evidence that the copy number variation (CNV) of the repeat units is a novel factor modulating the stress response and, thus, has phenotypic manifestations. The ribosomal repeat copy number plays a role in stress resistance, lifespan, in vitro fertilization chances, disease progression and aging, while the dynamics of the satellite copy number are a sort of indicator of the current stress state. Here, we review some facts showing that a combined assay of rDNA and SatII/III abundance can provide valuable individual data (“stress profile”) indicating not only the inherited adaptive reserve but also the stress duration and acute or chronic character of the stress. Thus, the repeat count could have applications in personalized medicine in the future. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

21 pages, 652 KiB

Open AccessFeature PaperReview

Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy

by Yung-Chun Wang, Yuchang Wu, Julie Choi, Garrett Allington, Shujuan Zhao, Mariam Khanfar, Kuangying Yang, Po-Ying Fu, Max Wrubel, Xiaobing Yu, Kedous Y. Mekbib, Jack Ocken, Hannah Smith, John Shohfi, Kristopher T. Kahle, Qiongshi Lu and Sheng Chih Jin

J. Pers. Med. 2022, 12(2), 175; https://doi.org/10.3390/jpm12020175 - 27 Jan 2022

Cited by 6 | Viewed by 7085

Abstract

Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative [...] Read more.

Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative for researchers to understand the resources and methodologies available for various data types and study designs. In this review, we provide an overview of recent methods for identifying rare and common variants and understanding their roles in disease etiology. Additionally, we discuss the strategy, challenge, and promise of gene therapy. As computational and statistical approaches continue to improve, we will have an opportunity to translate human genetic findings into personalized health care. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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Other

Jump to: Research, Review

8 pages, 416 KiB

Open AccessCase Report

Pharmacogenomics and Drug-Induced Phenoconversion Informed Medication Safety Review in the Management of Pain Control and Quality of Life: A Case Report

by Selina Muhn, Nishita Shah Amin, Chandni Bardolia, Nicole Del Toro-Pagán, Katie Pizzolato, David Thacker, Jacques Turgeon, Crystal Tomaino and Veronique Michaud

J. Pers. Med. 2022, 12(6), 974; https://doi.org/10.3390/jpm12060974 - 15 Jun 2022

Cited by 1 | Viewed by 2977

Abstract

Utilizing pharmacogenomics (PGx) and integrating drug-induced phenoconversion to guide opioid therapies could improve the treatment response and decrease the occurrence of adverse drug events. Genetics contribute to the interindividual differences in opioid response. The purpose of this case report highlights the impact of [...] Read more.

Utilizing pharmacogenomics (PGx) and integrating drug-induced phenoconversion to guide opioid therapies could improve the treatment response and decrease the occurrence of adverse drug events. Genetics contribute to the interindividual differences in opioid response. The purpose of this case report highlights the impact of a PGx-informed medication safety review, assisted by a clinical decision support system, in mitigating the drug–gene and drug–drug–gene interactions (DGI and DDGI, respectively) that increase the risk of an inadequate drug response and adverse drug events (ADEs). This case describes a 69-year-old female who was referred for PGx testing for uncontrolled chronic pain caused by osteoarthritis and neuropathy. The clinical pharmacist reviewed the PGx test results and medication regimen and identified several (DGIs and DDGIs, respectively) at Cytochrome P450 (CYP) 2C19 and CYP2D6. The recommendations were to: (1) switch tramadol to buprenorphine transdermal patch, an opioid with lower potential for ADEs, to mitigate a CYP2D6 DDGI; (2) gradually discontinue amitriptyline to alleviate the risk of anticholinergic side effects, ADEs, and multiple DDGIs; and (3) optimize the pregabalin. The provider and the patient agreed to implement these recommendations. Upon follow-up one month later, the patient reported an improved quality of life and pain control. Following the amitriptyline taper, the patient experienced tremors in the upper and lower extremities. When the perpetrator drug, omeprazole, was stopped, the metabolic capacity was no longer impeded; the patient experienced possible amitriptyline withdrawal symptoms due to the rapid withdrawal of amitriptyline, which was reinitiated and tapered off more slowly. This case report demonstrates a successful PGx-informed medication safety review that considered drug-induced phenoconversion and mitigated the risks of pharmacotherapy failure, ADEs, and opioid misuse. Full article

(This article belongs to the Special Issue From Prediction to Diagnosis: The Application of Genomics in Personalized Medicine)

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