Rates and Classification of Variants of Uncertain Significance in Hereditary Disease Genetic Testing

JAMA Network Open, Год журнала: 2023, Номер 6(10), С. e2339571 - e2339571

Опубликована: Окт. 25, 2023

Variants of uncertain significance (VUSs) are rampant in clinical genetic testing, frustrating clinicians, patients, and laboratories because the uncertainty hinders diagnoses management. A comprehensive assessment VUSs across many disease genes is needed to guide efforts reduce uncertainty.To describe sources, gene distribution, population-level attributes evaluate impact different types evidence used reclassify them.This cohort study germline DNA variant data from individuals referred by clinicians for diagnostic testing hereditary disorders. Participants included whom panel was conducted between September 9, 2014, 7, 2022. Data were analyzed 1, 2022, April 2023.The outcomes interest VUS rates (stratified age; clinician-reported race, ethnicity, ancestry groups; panels; attributes), percentage reclassified as benign or likely vs pathogenic pathogenic, enrichment reclassifying VUSs.The 1 689 845 ranging age 0 89 years at time (median age, 50 years), with 203 210 (71.2%) female individuals. There 39 150 Ashkenazi Jewish (2.3%), 64 730 Asian (3.8%), 126 739 Black (7.5%), 5539 French Canadian (0.3%), 169 714 Hispanic (10.0%), 5058 Native American 2696 Pacific Islander (0.2%), 4842 Sephardic 974 383 White (57.7%). Among all tested, 692 227 (41.0%) had least 535 385 (31.7%) only results. The number per individual increased more most missense changes (86.6%). More observed sequenced who not a European population, middle-aged older adults, underwent disorders incomplete penetrance. Of 37 699 unique that reclassified, 30 239 (80.2%) ultimately categorized benign. mean (SD) 30.7 (20.0) months elapsed be benign, 22.4 (18.9) pathogenic. Clinical contributed reclassification.This approximately 1.6 million highlighted need better methods interpreting variants, availability experimental classification, diverse representation groups genomic databases. this could provide sound basis understanding sources resolution navigating appropriate next steps patient care.

Язык: Английский

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Personalized Nutrition: Tailoring Dietary Recommendations through Genetic Insights

Nutrients, Год журнала: 2024, Номер 16(16), С. 2673 - 2673

Опубликована: Авг. 13, 2024

Personalized nutrition (PN) represents a transformative approach in dietary science, where individual genetic profiles guide tailored recommendations, thereby optimizing health outcomes and managing chronic diseases more effectively. This review synthesizes key aspects of PN, emphasizing the basis responses, contemporary research, practical applications. We explore how differences influence metabolisms, thus underscoring importance nutrigenomics developing personalized guidelines. Current research PN highlights significant gene–diet interactions that affect various conditions, including obesity diabetes, suggesting interventions could be precise beneficial if they are customized to profiles. Moreover, we discuss implementations technological advancements testing enable real-time customization. Looking forward, this identifies robust integration bioinformatics genomics as critical for advancing PN. advocate multidisciplinary overcome current challenges, such data privacy ethical concerns associated with testing. The future lies broader adoption across wellness sectors, promising public medicine.

Язык: Английский

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Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review

npj Genomic Medicine, Год журнала: 2024, Номер 9(1)

Опубликована: Фев. 27, 2024

Abstract Single locus (Mendelian) diseases are a leading cause of childhood hospitalization, intensive care unit (ICU) admission, mortality, and healthcare cost. Rapid genome sequencing (RGS), ultra-rapid (URGS), rapid exome (RES) diagnostic tests for genetic ICU patients. In 44 studies children in ICUs with unknown etiology, 37% received diagnosis, 26% had consequent changes management, net costs were reduced by $14,265 per child tested URGS, RGS, or RES. URGS outperformed RGS RES faster time to higher rate diagnosis clinical utility. Diagnostic outcomes will improve as methods evolve, decrease, testing is implemented within precision medicine delivery systems attuned needs. currently performed <5% the ~200,000 likely benefit annually due lack payor coverage, inadequate reimbursement, hospital policies, hospitalist unfamiliarity, under-recognition possible diseases, current formatting rather than system. The gap between actual optimal increasing since expanded use lags growth those through new therapies. There sufficient evidence conclude that should be considered all uncertain etiology at admission. Minimally, ordered early during admissions critically ill infants suspected diseases.

Язык: Английский

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Artificial intelligence in clinical genetics

European Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 13, 2025

Abstract Artificial intelligence (AI) has been growing more powerful and accessible, will increasingly impact many areas, including virtually all aspects of medicine biomedical research. This review focuses on previous, current, especially emerging applications AI in clinical genetics. Topics covered include a brief explanation different general categories AI, machine learning, deep generative AI. After introductory explanations examples, the discusses genetics three main categories: diagnostics; management therapeutics; support. The concludes with short, medium, long-term predictions about ways that may affect field Overall, while precise speed at which continue to change is unclear, as are overall ramifications for patients, families, clinicians, researchers, others, it likely result dramatic evolution It be important those involved prepare accordingly order minimize risks maximize benefits related use field.

Язык: Английский

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Pathophysiology of human hearing loss associated with variants in myosins

Frontiers in Physiology, Год журнала: 2024, Номер 15

Опубликована: Март 18, 2024

Deleterious variants of more than one hundred genes are associated with hearing loss including MYO3A , MYO6 MYO7A and MYO15A two conventional myosins MYH9 MYH14 . Variants also manifest as Usher syndrome dysfunction the retina vestibule well loss. While functions in inner ear debated, MYO3A, MYO6, expressed hair cells along class-I myosin MYO1C essential for developing maintaining functional stereocilia on apical surface cells. Stereocilia large, cylindrical, actin-rich protrusions functioning biological mechanosensors to detect sound, acceleration posture. The rigidity is sustained by highly crosslinked unidirectionally-oriented F-actin, which provides a scaffold various proteins unconventional their cargo. Typical molecules consist an ATPase head motor domain transmit forces neck containing IQ-motifs that bind regulatory light chains tail region motifs recognizing partners. Instead long coiled-coil domains characterizing myosins, tails have anchor or transport phospholipids F-actin core stereocilium. For these decades studies elucidated biochemical properties, interacting partners However, less known about how traffic stereocilium using function, each variant correlates clinical condition severity onset loss, mode inheritance presence symptoms other Here, we cover structures together advances, open questions trafficking correlations between hundreds annotated ClinVar corresponding deafness phenotypes.

Язык: Английский

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Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(9), С. 2544 - 2544

Опубликована: Апрель 26, 2024

Congenital heart disease (CHD) and cardiomyopathies are the leading cause of morbidity mortality worldwide. These conditions often caused by genetic factors, recent research has shown that genomic testing can provide valuable information for patient care. By identifying causes, healthcare providers screen other related health conditions, offer early interventions, estimate prognosis, select appropriate treatments, assess risk family members. Genetic is now standard care in patients with CHD cardiomyopathy. However, rapid advances technology greater availability options have led to changes recommendations most method. Several studies investigated utility this changing landscape. This review summarizes literature surrounding clinical evaluation

Язык: Английский

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Clinical Variant Reclassification in Hereditary Disease Genetic Testing

JAMA Network Open, Год журнала: 2024, Номер 7(11), С. e2444526 - e2444526

Опубликована: Ноя. 6, 2024

Importance Because accurate and consistent classification of DNA sequence variants is fundamental to germline genetic testing, understanding patterns initial variant (VC) subsequent reclassification from large-scale, empirical data can help improve VC methods, promote equity among race, ethnicity, ancestry (REA) groups, provide insights inform clinical practice. Objectives To measure the degree which VCs met certainty thresholds set by professional guidelines quantify rates of, factors associated with, impact more than 2 million variants. Design, Setting, Participants This cohort study used multigene panel exome sequencing diagnostic testing for hereditary disorders, carrier screening, or preventive screening individuals whom was performed between January 1, 2015, June 30, 2023. Exposure were classified into 1 5 categories: benign, likely uncertain significance (VUS), pathogenic, pathogenic. Main Outcomes Measures The main outcomes accuracy classifications, directions reclassifications, evidence contributing their across different areas REA groups. One-way analysis variance followed post hoc pairwise Tukey honest significant difference tests analyze differences means, Pearson χ with Bonferroni corrections compare categorical variables Results comprised 3 272 035 (median [range] age, 44 [0-89] years; 240 506 female [68.47%] 030 729 male [31.50%]; 216 752 Black [6.62%]; 336 414 Hispanic [10.28%]; 804 273 White [55.14%]). Among 051 736 observed over 8 years in this cohort, 94 453 (4.60%) reclassified. Some reclassified once, resulting 105 172 total events. majority (64 events [61.65%]) changes VUS either pathogenic categories. An additional 37.66% reclassifications (39 608 events) gains terminal categories (ie, benign pathogenic). Only a small fraction (663 [0.63%]) moved toward less certainty, very rarely (61 [0.06%]) reversals. When normalized number tested, higher specific underrepresented populations (Ashkenazi Jewish, Asian, Black, Hispanic, Pacific Islander, Sephardic Jewish). Approximately one-half (37 074 64 840 [57.18%]) resulted improved use computational modeling. Conclusions Relevance In undergoing empirically estimated classifications exceeded current guidelines, suggesting need reevaluate definitions these classifications. relative contribution various strategies resolve VUS, including emerging machine learning–based RNA analysis, cascade family provides useful that be applied further improving reducing rate generating definitive results patients.

Язык: Английский

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A Perspective on Artificial Intelligence for Molecular Pathologists

Journal of Molecular Diagnostics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Cutting-edge AI tools revolutionizing scientific research in life sciences

BioTechnologia, Год журнала: 2025, Номер unknown

Опубликована: Март 7, 2025

Artificial intelligence (AI) is becoming a transformative force in the life sciences, pushing boundaries of possibility. Imagine AI automating time-consuming tasks, uncovering hidden patterns vast datasets, designing proteins minutes instead years, and even predicting disease outbreaks before they occur. This review explores latest tools revolutionizing scientific fields, including research data analysis, healthcare, supporting writing. Beyond processing, reshaping how scientists draft share their findings, enhancing processes ranging from literature reviews to citation management. However, with great power comes responsibility. Are we prepared for this leap? delves into forefront where innovation meets

Язык: Английский

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SITC strategic vision: prevention, premalignant immunity, host and environmental factors

Journal for ImmunoTherapy of Cancer, Год журнала: 2025, Номер 13(3), С. e010419 - e010419

Опубликована: Март 1, 2025

Cancer immunotherapy has improved the survival of a subset patients by harnessing power immune system to find and destroy malignant cells. The also protects host destroying developing premalignant tumors. Advancing our knowledge immunity changes seen in lesions that develop into invasive cancer versus those regress offers an exciting opportunity leverage for prevention interception premalignancy. Understanding environment how chronic inflammation plays central role evolution premalignancy is essential effective immunoprevention interceptions. Factors such as genomics environmental factors affect outcome advanced cancers are equally important determining response immunotherapy. broad use antibiotics obesity can disrupt healthy gut microbiome drive suppresses preventive or antitumor required successful cancers. Modifiable lifestyle diet, obesity, smoking, stress should be considered designing studies, well who receive treatment. Other factors, overall health existing comorbidities, both and, therefore, managing with without cancer. Society Immunotherapy previously developed overarching manuscript regarding challenges opportunities exist immunotherapy, this serves in-depth follow-up topics immunity, interception, immunoprevention, impact on responding

Язык: Английский

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