Era Of Genomic Medicine Research Articles

Eleven Grand Challenges for Inflammatory Bowel Disease Genetics and Genomics

Abstract The past 2 decades have witnessed extraordinary advances in our understanding of the genetic factors influencing inflammatory bowel disease (IBD), providing a foundation for the approaching era of genomic medicine. On behalf of the NIDDK IBD Genetics Consortium, we herein survey 11 grand challenges for the field as it embarks on the next 2 decades of research utilizing integrative genomic and systems biology approaches. These involve elucidation of the genetic architecture of IBD (how it compares across populations, the role of rare variants, and prospects of polygenic risk scores), in-depth cellular and molecular characterization (fine-mapping causal variants, cellular contributions to pathology, molecular pathways, interactions with environmental exposures, and advanced organoid models), and applications in personalized medicine (unmet medical needs, working toward molecular nosology, and precision therapeutics). We review recent advances in each of the 11 areas and pose challenges for the genetics and genomics communities of IBD researchers.

Early Intervention services in the era of genomic medicine: setting a research agenda.

Newborn genomic sequencing (NBSeq) has the potential to substantially improve early detection of rare genetic conditions, allowing for pre-symptomatic treatment to optimize outcomes. Expanding conceptions of the clinical utility of NBSeq include earlier access to behavioral early intervention to support the acquisition of core motor, cognitive, communication, and adaptive skills during critical windows in early development. However, important questions remain about equitable access to early intervention programs for the growing number of infants identified with a genetic condition via NBSeq. We review the current NBSeq public health, clinical, and research landscape, and highlight ongoing international research efforts to collect population-level data on the utility of NBSeq for healthy newborns. We then explore the challenges facing a specific Early Intervention (EI) system-the US federally supported "Part C" system-for meeting the developmental needs of young children with genetic diagnoses, including structural limitations related to funding, variable eligibility criteria, and lack of collaboration with newborn screening programs. We conclude with a set of questions to guide future research at the intersection of NBSeq, newborn screening, and EI, which once answered, can steer future policy to ensure that EI service systems can optimally support the developmental needs of infants impacted by broader implementation of NBSeq. IMPACT: Existing literature on the clinical benefits of genome sequencing in newborns tends to focus on earlier provision of medical interventions, with less attention to the ongoing developmental needs of very young children with genetic conditions. This review outlines the developmental needs of a growing number of children diagnosed with genetic conditions in infancy and describes the strengths and limitations of the United States Early Intervention system (IDEA Part C) for meeting those needs.

AML Treatment Options Expand in Era of Genomic Medicine

AML Treatment Options Expand in Era of Genomic Medicine

Towards genomic medicine: a tailored next-generation sequencing panel for hydroxyurea pharmacogenomics in Tanzania

BackgroundPharmacogenomics of hydroxyurea is an important aspect in the management of sickle cell disease (SCD), especially in the era of genomic medicine. Genetic variations in loci associated with HbF induction and drug metabolism are prime targets for hydroxyurea (HU) pharmacogenomics, as these can significantly impact the therapeutic efficacy and safety of HU in SCD patients.MethodsThis study involved designing of a custom panel targeting BCL11A, ARG2, HBB, HBG1, WAC, HBG2, HAO2, MYB, SAR1A, KLF10, CYP2C9, CYP2E1 and NOS1 as potential HU pharmacogenomics targets. These genes were selected based on their known roles in HbF induction and HU metabolism. The panel was designed using the Illumina Design Studio (Illumina, San Diego, CA, USA) and achieved a total coverage of 96% of all genomic targets over a span of 51.6 kilobases (kb). This custom panel was then sequenced using the Illumina MiSeq platform to ensure high coverage and accuracy.ResultsWe are reporting a successfully designed Illumina (MiSeq) HU pharmacogenomics custom panel encompassing 51.6 kilobases. The designed panel achieved greater than 1000x amplicon coverage which is sufficient for genomic analysis.ConclusionsThis study provides a valuable tool for research in HU pharmacogenomics, especially in Africa where SCD is highly prevalent, and personalized medicine approaches are crucial for improving patient outcomes. The custom-designed Illumina (MiSeq) panel, with its extensive coverage and high sequencing depth, provides a robust platform for studying genetic variations associated with HU response. This panel can contribute to the development of tailored therapeutic strategies, ultimately enhancing the management of SCD through more effective and safer use of hydroxyurea.

Whole-genome sequences reveal zygotic composition in chimeric twins

While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin family to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine.

Current status and prospects of genetic research on IgA nephropathy

IgA nephropathy is the most common primary glomerulonephritis worldwide, and genetic factors may play an important role in its pathogenesis. Following candidate gene association analysis and genome-wide linkage study, genome-wide association studies (GWAS) have found multiple susceptibility genes related to the pathogenesis and clinical phenotype of IgA nephropathy. Meanwhile, structural variation and epigenetic changes are also closely related to IgA nephropathy. Genetic variants have been found to explain about 11% of its heritability. In the current era of genomic medicine, how to find more susceptible genes/loci, whole genome sequencing studies (WGS) provide clues to further understand the genetic variation of IgA nephropathy. How to find the cell type-specific susceptibility genes associated with IgA nephropathy, multi-omics studies will conduct comprehensive analysis via single-cell sequencing, expression quantitative trait locus (eQTL) and genomics to find the pathogenic genes and offer insights into the development of targeted drugs, which will be the trend and direction of future research.

Precision Population Cancer Medicine in Cancer of the Uterine Cervix: A Potential Roadmap to Eradicate Cervical Cancer.

With the success of the Human Genome Project, the era of genomic medicine (GM) was born. Later on, as GM made progress, there was a feeling of exhilaration that GM could help resolve many disease processes. It also led to the conviction that personalized medicine was possible, and a relatively synonymous word, precision medicine (PM), was coined. However, the influence of environmental factors and social determinants of diseases was only partially given their due importance in the definition of PM, although more recently, this has been recognized. With the rapid advances in GM, big data, data mining, wearable devices for health monitoring, telemedicine, etc., PM can be more easily extended to population-level health care in disease management, prevention, early screening, and so on.and the term precision population medicine (PPM) more aptly describes it. PPM's potential in cancer care was posited earlier,and the current authors planned a series of cancer disease-specific follow-up articles. These papers are mainly aimed at helping emerging students in health sciences (medicine, pharmacy, nursing, dentistry, public health, population health), healthcare management (health-focused business administration, nonprofit administration, public institutional administration, etc.), and policy-making (e.g., political science), although not exclusively. This first disease-specific report focuses on the cancer of the uterine cervix (CC). It describes how recent breakthroughs can be leveraged as force multipliers to improve outcomes in CC - by improving early detection, better screening for CC, potential GM-based interventions during the stage of persistent Human papillomavirus (HPV) infection and treatment interventions - especially among the disadvantaged and resource-scarce populations. This work is a tiny step in our attempts to improve outcomes in CC and ultimately eradicate CC from the face of the earth.

Implementing mainstream genetic counseling within the area-wide network of the German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC): Satisfaction of primary care providers with the provided state-of-the-art training by the Cologne Center.

The German Cancer Society (Deutsche Krebsgesellschaft DKG) has published a position paper to address the challenges of cancer patient care in the era of genomic medicine. The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) has implemented this recommendation in its care concept for families at risk. Core elements are the outcome-oriented evaluation of structured and standardized clinical measures and reporting recommendations derived therefrom to primary care providers and patients. A cross-sector network with certified breast cancer and gynecological cancer centers was founded in 2015, starting from the Cologne Center of the GC-HBOC. To guarantee the knowledge transfer for mainstream genetic counseling, the Cologne center has established an educational program for physicians and specialized nurses in order to pilot trans-sectoral knowledge transfer on risk assessment and risk-stratified care. It consists of face-to-face lectures with written knowledge test, attending a genetic case conference and genetic counseling sessions with the opportunity to counsel under supervision. The lectures were accompanied by a structured evaluation of the participants' satisfaction and feedback of the needs in mainstream genetic counseling. Thereby, the network ensures that genetic counseling and testing is provided according to state-of-the-art knowledge and allows physicians to participate in knowledge-generating care outside the university setting and patients to receive care close to home. After multiple feedback cycles to improve the educational program, the GC-HBOC, in cooperation with the German Cancer Society, has now adopted this concept and developed a common and uniform online curriculum funded by the Federal Ministry of Health. https://www.krebsgesellschaft.de/fortbildung-familiaerer-krebs.html.

Challenges in molecular diagnosis of multiple endocrine neoplasia.

Multiple endocrine neoplasia (MEN) is a group of rare genetic diseases characterized by the occurrence of multiple tumors of the endocrine system in the same patient. The first MEN described was MEN1, followed by MEN2A, and MEN2B. The identification of the genes responsible for these syndromes led to the introduction of family genetic screening programs. More than twenty years later, not all cases of MENs have been resolved from a genetic point of view, and new clinicogenetic entities have been described. In this review, we will discuss the strategies and difficulties of genetic screening for classic and newly described MENs in a clinical setting, from limitations in sequencing, to problems in classifying variants, to the identification of new candidate genes. In the era of genomic medicine, characterization of new candidate genes and their specific tumor risk is essential for inclusion of patients in personalized medicine programs as well as to permit accurate genetic counseling to be proposed for families.

Exploring the evolving roles of clinical geneticists and genetic counselors in the era of genomic medicine.

The increased utilization of clinical genomic sequencing in the past decade has ushered in the era of genomic medicine, requiring genetics providers to acquire new skills and adapt their practices. The change in workplace responsibilities of clinical/medical geneticists (CMGs) and genetic counselors (GCs) in North America, due to the evolution of genetic testing, has not been studied. We surveyed CMGs (n = 80) and GCs (n = 127) with experience in general/pediatric genetics to describe their current practice of clinical tasks and the change in regularity of performing these tasks over the past 5-10 years. Currently, complementarity of responsibilities between CMGs and GCs clearly exists but providers who have been in the field for longer have noted role changes. Trends indicate that fewer experienced CMGs perform physical exams and select genetic tests than before and fewer experienced GCs complete requisitions and write result letters. The frequency of CMGs and GCs who investigate genetic test results, however, has increased. This study provides insight into the changing landscape of clinical genetics practice. Our findings suggest that the roles and responsibilities of CMGs and GCs have shifted in the past decade.

Exploring the training needs of inherited cardiac conditions (ICC) nurses: Elucidating role boundaries and competencies for practice in the genomics era.

Nurses represent the largest professional group within the National Health Service (NHS) and are therefore central to the successful integration of mainstreaming genomics into routine healthcare. Inherited cardiac conditions (ICC) nurse roles have been developed in recent years to streamline the care for patients and families affected by an ICC. Like many nurse specialists, ICC nurses' prior exposure to genomics and the wider implications surrounding inherited conditions is limited. The aim of the study was to explore the education needs and support required for ICC nurses to fulfill their role within the genomic medicine era. A convenience sampling approach was adopted to invite ICC nurses working within various NHS Trusts across the United Kingdom to take part. Semi-structured interviews were conducted with ICC nurses (n = 8), which were recorded, transcribed, coded, and analyzed using an inductive thematic analysis approach. Analysis of interview data highlighted four core themes, which were transferrable core competencies; managing genomic information; mixed-modality learning; defining multidisciplinary team boundaries. The study highlights areas for further training and demonstrates the importance of defining competencies and role boundaries within ICC services. The ICC nurses identified the limits of their practice and the complementary role of genetic counselors, indicating the need for both professions within the ICC service and proposing implications for practice.

Clinical applications of next-generation sequencing in the diagnosis of genetic disorders in Korea: a narrative review

Background: Next-generation sequencing (NGS) technologies have revolutionized genetic testing and enabled efficient screening of various genetic conditions in clinical settings. However, the clinical application of genetic test results presents numerous significant challenges. This review aims to provide a comprehensive overview of key concepts for the clinical application of NGS, including (1) technical aspects and limitations, (2) variant classification, (3) clinical interpretation, (4) familial testing and genetic counseling, and (5) ethical considerations.Current Concepts: In short-read-based NGS, several limitations exist in detecting genomic variations, including repetitive sequences or complex structural variations. The variant classification process can be influenced by suspected genomic conditions and the accessibility of genomic databases. Therefore, the final genetic diagnosis depends on the physician’s discretion, which relies on the genotype-phenotype correlations and reverse phenotyping through additional evaluations. Familial testing can help trace the origin of variants and allele segregation and aid in variant interpretation, risk assessment, disease prevention, and family planning. In addition to addressing the clinical impact of genetic results, genetic counselors should also consider potential consequences related to ethical, legal, and social issues, including family dynamics.Discussion and Conclusion: NGS-based genetic testing is a promising diagnostic tool for genetic disorders, but proper variant interpretation and clinical evaluation are crucial for optimal clinical practice. Notably, ethical considerations and regulatory measures are required to prepare for the next era of genomic medicine.

Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum.

Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes. The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS. The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31 of 114 GDRs curated (27%), moderate for 38 (33%), limited for 43 (38%), and disputed for 2 (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 were autosomal dominant, and 3 were X-linked. GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multisystem organ surveillance, recurrence risk counseling, reproductive choice, natural history studies, and determination of eligibility for interventional clinical trials. ANN NEUROL 2023;94:696-712.

The genetic counselor: recognizing their critical role in neurology clinics in the era of genomic medicine (P12-4.001)

<h3>Objective:</h3> To describe the critical role of the clinical genetic counselor in the neurology setting and their impact on patient care. <h3>Background:</h3> Genetic testing is increasingly utilized in the diagnosis of neurodegenerative disorders. This is particularly relevant as the field moves towards neurogenetic intervention. Determining who should be genetically tested, which tests should be performed, which labs are most appropriate and how to secure insurance coverage for patients with neurological conditions remains a challenge. Reviewing the complexity of testing options and potential impact of the results on patients and family members is also time-consuming and can be a barrier to care when physicians are required to fill this role unassisted by clinical professionals with targeted genetic expertise. Genetic counselors are healthcare professionals with specialized training in medical genetics and psychosocial counseling who can solve this challenge in clinical care. <h3>Design/Methods:</h3> Here we describe the role and impact of genetic counselor in the Massachusetts General Hospital Ataxia Center as a case in point. <h3>Results:</h3> The genetic counselor’s primarily roles are in pretest and posttest counseling. Pretest counseling includes comprehensive genetic evaluations and determining appropriate genetic testing pathways for individuals with suspected hereditary ataxic disorders. They review test benefits, limitations, and risks, impacts on patients and family members, and facilitate prior authorizations for insurance approval and test orders. Posttest counseling involves disclosure of sensitive results in the context of the patient’s medical and family history, and incudes psychosocial support. Follow up includes connecting patients to resources and support groups, arranging family segregation studies in case of uncertain results, and cascade testing for at risk relatives. <h3>Conclusions:</h3> The genetic counselor’s knowledge and counseling skills help improve patient care, optimize physician time, focus the testing strategy, and reduce costs. Genetic counselors are integral members of the multidisciplinary neurology team in the era of genomic medicine. <b>Disclosure:</b> Ms. Chen has nothing to disclose. Dr. Schmahmann has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medavante. Dr. Schmahmann has stock in Cadent. The institution of Dr. Schmahmann has received research support from National Ataxia Foundation. The institution of Dr. Schmahmann has received research support from Biohaven. Dr. Schmahmann has received intellectual property interests from a discovery or technology relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care. Dr. Schmahmann has received publishing royalties from a publication relating to health care.

Variant Landscape of 15 Genes Involved in Corneal Dystrophies: Report of 30 Families and Comprehensive Analysis of the Literature

Corneal dystrophies (CDs) represent a group of inherited diseases characterized by the progressive deposit of abnormal materials in the cornea. This study aimed to describe the variant landscape of 15 genes responsible for CDs based on a cohort of Chinese families and a comparative analysis of literature reports. Families with CDs were recruited from our eye clinic. Their genomic DNA was analyzed using exome sequencing. The detected variants were filtered using multi-step bioinformatics and confirmed using Sanger sequencing. Previously reported variants in the literature were summarized and evaluated based on the gnomAD database and in-house exome data. In 30 of 37 families with CDs, 17 pathogenic or likely pathogenic variants were detected in 4 of the 15 genes, including TGFBI, CHST6, SLC4A11, and ZEB1. A comparative analysis of large datasets revealed that 12 of the 586 reported variants are unlikely causative of CDs in monogenic mode, accounting for 61 of 2933 families in the literature. Of the 15 genes, the gene most frequently implicated in CDs was TGFBI (1823/2902, 62.82% of families), followed by CHST6 (483/2902, 16.64%) and SLC4A11 (201/2902, 6.93%). This study presents, for the first time, the landscape of pathogenic and likely pathogenic variants in the 15 genes responsible for CDs. Awareness of frequently misinterpreted variants, such as c.1501C>A, p.(Pro501Thr) in TGFBI, is crucial in the era of genomic medicine.

Reducing uncertainty in genetic testing with Saturation Genome Editing.

Accurate interpretation of human genetic data is critical for optimizing outcomes in the era of genomic medicine. Powerful methods for testing genetic variants for functional effects are allowing researchers to characterize thousands of variants across disease genes. Here, we review experimental tools enabling highly scalable assays of variants, focusing specifically on Saturation Genome Editing (SGE). We discuss examples of how this technique is being implemented for variant testing at scale and describe how SGE data for BRCA1 have been clinically validated and used to aid variant interpretation. The initial success at predicting variant pathogenicity with SGE has spurred efforts to expand this and related techniques to many more genes.

Adjuvant Therapy in Node-Positive Endometrial Cancer: A Focus on Chemotherapy.

In advanced-stage and high-risk endometrial cancer, adjuvant treatment is the standard of care and typically includes chemotherapy with or without radiotherapy. Debate continues over the optimal use of these two treatment modalities together or separately. This review covers the historical literature leading to the current recommendation for adjuvant chemotherapy, in addition to looking forward to the relatively new field of targeted molecular treatment. The review covers recent phase III trials comparing chemotherapy to radiotherapy in high-risk endometrial cancer. Additionally, the era of genomic medicine has a new foothold in endometrial cancer, and the review covers new discoveries on molecular classification and prognostic implications. Fortunately, the majority of endometrial cancer has a good prognosis. For advanced-stage and high-risk histologies, the prognosis can be guarded, with adjuvant treatment improving outcomes. Gynecologic oncologists continue to debate the optimal treatment modality/modalities, a debate which will likely become more robust as the field of molecular treatment in endometrial cancer evolves.

SPiP: Splicing Prediction Pipeline, a machine learning tool for massive detection of exonic and intronic variant effects on mRNA splicing.

Modeling splicing is essential for tackling the challenge of variant interpretation as each nucleotide variation can be pathogenic by affecting pre-mRNA splicing via disruption/creation of splicing motifs such as 5'/3' splice sites, branch sites, or splicing regulatory elements. Unfortunately, most in silico tools focus on a specific type of splicing motif, which is why we developed the Splicing Prediction Pipeline (SPiP) to perform, in one single bioinformatic analysis based on a machine learning approach, a comprehensive assessment of the variant effect on different splicing motifs. We gathered a curated set of 4616 variants scattered all along the sequence of 227 genes, with their corresponding splicing studies. The Bayesian analysis provided us with the number of control variants, that is, variants without impact on splicing, to mimic the deluge of variants from high-throughput sequencing data. Results show that SPiP can deal with the diversity of splicing alterations, with 83.13% sensitivity and 99% specificity to detect spliceogenic variants. Overall performance as measured by area under the receiving operator curve was 0.986, better than SpliceAI and SQUIRLS (0.965 and 0.766) for the same data set. SPiPlends itself to a unique suite for comprehensive prediction of spliceogenicity in the genomic medicine era. SPiP is available at: https://sourceforge.net/projects/splicing-prediction-pipeline/.

The Genetic Architecture of the Etiology of Lower Extremity Peripheral Artery Disease: Current Knowledge and Future Challenges in the Era of Genomic Medicine.

Lower extremity artery disease (LEAD), caused by atherosclerotic obstruction of the arteries of the lower limb extremities, has exhibited an increase in mortality and morbidity worldwide. The phenotypic variability of LEAD is correlated with its complex, multifactorial etiology. In addition to traditional risk factors, it has been shown that the interaction between genetic factors (epistasis) or between genes and the environment potentially have an independent role in the development and progression of LEAD. In recent years, progress has been made in identifying genetic variants associated with LEAD, by Genome-Wide Association Studies (GWAS), Whole Exome Sequencing (WES) studies, and epigenetic profiling. The aim of this review is to present the current knowledge about the genetic factors involved in the etiopathogenic mechanisms of LEAD, as well as possible directions for future research. We analyzed data from the literature, starting with candidate gene-based association studies, and then continuing with extensive association studies, such as GWAS and WES. The results of these studies showed that the genetic architecture of LEAD is extremely heterogeneous. In the future, the identification of new genetic factors will allow for the development of targeted molecular therapies, and the use of polygenic risk scores (PRS) to identify individuals at an increased risk of LEAD will allow for early prophylactic measures and personalized therapy to improve their prognosis.

Challenges for precision public health communication in the era of genomic medicine

Although still in the early stages of development, the advent of fast, high-output, and cost-effective next-generation DNA sequencing technology is moving precision medicine into public health. Before this shift toward next-generation sequencing in public health settings, individual patients met geneticists after showing symptoms and through limited family screening. In the new era of precision public health, everyone is a possible participant in genetic sequencing, simply by being born (newborn screening), by donating blood (biobanking), or through population screening. These initiatives are increasingly offered to individuals throughout their life and more individuals are encountering opportunities to use DNA sequencing. This article raises awareness of these growing areas and calls for different models of public engagement and communication about genomics, including screening asymptomatic populations, obtaining consent for unspecified and unforeseen future uses of genomic data, and managing variants of uncertain significance. Given that such communication challenges loom large, established norms of practice in genomic medicine and research should be reconsidered.