657 hot topic(s) found with the query "Genome sequencing"
Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for pediatric diagnostic testing
(Posted: Apr 29, 2024 11AM)
From the abstract: "Measuring effects of genomic sequencing (GS) on patients and families is critical for translational research. We aimed to develop and validate an instrument to assess parents’ perceived utility of pediatric diagnostic GS. Methods: Informed by a five-domain conceptual model, the study comprised five steps: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. "
Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal
(Posted: Apr 19, 2024 10AM)
From the abstract: "Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered to research participants in order to demonstrate respect for autonomy, reciprocity, and participant interests in health and privacy."
Genomic Answers for Kids: Toward more equitable access to genomic testing for rare diseases in rural populations
(Posted: Apr 18, 2024 8AM)
From the abstract: "Next-generation sequencing has revolutionized the speed of rare disease (RD) diagnoses. While clinical exome and genome sequencing represent an effective tool for many RD diagnoses, there is room to further improve the diagnostic odyssey of many RD patients. One recognizable intervention lies in increasing equitable access to genomic testing. Rural communities represent a significant portion of underserved and underrepresented individuals facing additional barriers to diagnosis and treatment."
Role of next generation sequencing in diagnosis and management of critically ill children with suspected monogenic disorder
S Bahtia et al, EJHG, April 11, 2024
(Posted: Apr 12, 2024 9AM)
From the abstract: " Next generation sequencing based diagnosis has emerged as a promising tool for evaluating critically ill neonates and children. However, there is limited data on its utility in developing countries. We assessed its diagnostic rate and clinical impact on management of pediatric patients with a suspected genetic disorder requiring critical care. The study was conducted at a single tertiary hospital in Northern India. We analyzed 70 children with an illness requiring intensive care and obtained a precise molecular diagnosis in 32 of 70 probands (45.3%) using diverse sequencing techniques such as clinical exome, whole exome, and whole genome. A significant change in clinical outcome was observed in 13 of 32 (40.6%) diagnosed probands with a change in medication in 11 subjects and redirection to palliative care in two subjects."
A framework for the evaluation and reporting of incidental findings in clinical genomic testing
CM Brown et al, EJHG, April 2, 2024
(Posted: Apr 02, 2024 9AM)
From the abstract: "Herein we describe a framework developed to guide the evaluation and return of IFs encountered in probands undergoing clinical genome sequencing (cGS). The framework prioritizes clinical significance and actionability of IFs and follows a stepwise approach with stopping points at which IFs may be recommended for return or not. Over 18 months, implementation of the framework in a clinical laboratory facilitated the return of actionable IFs in 37 of 720 (5.1%) individuals referred for cGS. "
Comprehensive whole-genome sequence analyses provide insights into the genomic architecture of cerebral palsy.
Darcy L Fehlings et al. Nat Genet 2024 3
(Posted: Apr 01, 2024 9AM)
From the abstract: " We performed whole-genome sequencing (WGS) in 327 children with cerebral palsy (CP) and their biological parents. We classified 37 of 327 (11.3%) children as having pathogenic/likely pathogenic (P/LP) variants and 58 of 327 (17.7%) as having variants of uncertain significance. An enrichment analysis revealed previously undescribed plausible candidate CP genes (SMOC1, KDM5B, BCL11A and CYP51A1). A multifactorial CP risk profile and substantial presence of P/LP variants combine to support WGS in the diagnostic work-up across all CP and related phenotypes."
Advancing access to genome sequencing for rare genetic disorders: recent progress and call to action.
Vaidehi Jobanputra et al. NPJ Genom Med 2024 3 (1) 23
(Posted: Apr 01, 2024 9AM)
From the article: "GS has ushered in a new era in the diagnosis of genetic diseases, offering the potential for improved patient care. Now is the time for collective action to overcome challenges, implement best practices, and ensure that the benefits of GS are realized for all individuals affected by genetic diseases. Indeed, widespread and appropriate utilization of GS is critical for directing the emerging gene editing, gene therapy, and cell-based therapies for rare genetic disorders. Concerted policy, education, guideline, and care pathway efforts will drive significant advancements in precision medicine and improve health outcomes for patients with genetic conditions. "
Applications of genome sequencing as a single platform for clinical constitutional genetic testing
Y Yang et al, GIM Open, March 20, 2024
(Posted: Mar 27, 2024 1PM)
From the abstract: "The number of human disease genes has dramatically increased over the past decade, largely fueled by ongoing advances in sequencing technologies. In parallel, the number of available clinical genetic tests has also increased, including exome sequencing for undiagnosed diseases. Although most clinical sequencing tests have been centered on enrichment-based multigene panels and exome sequencing, the continued improvements in performance and throughput of genome sequencing suggest that this technology is emerging as a potential platform for routine clinical genetic testing. "
Genomes in clinical care
O Riess et al, NPJ Genomic Medicine, March 14, 2024
(Posted: Mar 18, 2024 9AM)
From the abstract: "In the era of precision medicine, genome sequencing (GS) has become more affordable and the importance of genomics and multi-omics in clinical care is increasingly being recognized. However, how to scale and effectively implement GS on an institutional level remains a challenge for many. Here, we present Genome First and Ge-Med, two clinical implementation studies focused on identifying the key pillars and processes that are required to make routine GS and predictive genomics a reality in the clinical setting. "
Viral genome sequencing to decipher in-hospital SARS-CoV-2 transmission events.
Elisabeth Esser et al. Sci Rep 2024 3 (1) 5768
(Posted: Mar 11, 2024 8AM)
From the abstract: "The SARS-CoV-2 pandemic has highlighted the need to better define in-hospital transmissions, a need that extends to all other common infectious diseases encountered in clinical settings. To evaluate how whole viral genome sequencing can contribute to deciphering nosocomial SARS-CoV-2 transmission 926 SARS-CoV-2 viral genomes from 622 staff members and patients were collected. Bioinformatically defined transmission clusters inferred from viral genome sequencing were compared to those inferred from interview-based contact tracing. Clustering analysis of SARS-CoV-2 whole genome sequences can reveal cryptic transmission events missed by classical, interview-based contact tracing, helping to decipher in-hospital transmissions. These results, in line with other studies, advocate for viral genome sequencing as a pathogen transmission surveillance tool in hospitals. "
Exome and genome sequencing in a heterogeneous population of patients with rare disease: Identifying predictors of a diagnosis
J Pucel et al, Genetics in Medicine, March 1, 2024
(Posted: Mar 01, 2024 0PM)
From the abstract: "In this case control study, we reviewed data from 400 diagnosed and 400 undiagnosed randomly selected participants in the Undiagnosed Diseases Network (UDN), all of whom had undergone ES and/or GS. We analyzed factors associated with receiving a diagnosis by ES and/or GS.
Factors associated with a decreased odds of being diagnosed included adult symptom onset, singleton sequencing, and having undergone ES and/or GS prior to acceptance to the UDN (48%, 51%, and 32% lower odds, respectively). Factors that increased the odds of being diagnosed by ES and/or GS included having primarily neurological symptoms and having undergone prior chromosomal microarray testing. "
Evidence review and considerations for use of first line genome sequencing to diagnose rare genetic disorders.
Kristen M Wigby et al. NPJ Genom Med 2024 2 (1) 15
(Posted: Feb 29, 2024 8AM)
From the abstract: "Seventy-one studies met inclusion criteria, comprising over 13,000 patients who received GS in one of the following settings: hospitalized pediatric patients, pediatric outpatients, adult outpatients, or mixed. GS was the first-line test in 38% (27/71). The unweighted mean DY of first-line GS was 45% (12–73%), 33% (6–86%) in cohorts with prior genetic testing, and 33% (9–60%) in exome-negative cohorts. Clinical utility was reported in 81% of first-line GS studies in hospitalized pediatric patients. "
Rapid genomic sequencing for genetic disease diagnosis and therapy in intensive care units: a review.
Stephen F Kingsmore et al. NPJ Genom Med 2024 2 (1) 17
(Posted: Feb 29, 2024 8AM)
From the abstract: " Rapid genome sequencing (RGS), ultra-rapid genome sequencing (URGS), and rapid exome sequencing (RES) are diagnostic tests for genetic diseases for ICU patients. In 44 studies of children in ICUs with diseases of unknown etiology, 37% received a genetic diagnosis, 26% had consequent changes in management, and net healthcare costs were reduced by $14,265 per child tested by URGS, RGS, or RES. URGS outperformed RGS and RES with faster time to diagnosis, and higher rate of diagnosis and clinical utility. "
3-hour genome sequencing and targeted analysis to rapidly assess genetic risk
M Galey et al, GIM Open, February 24, 2024
(Posted: Feb 27, 2024 9AM)
From the abstract: "This proof-of-concept experiment demonstrates how prior knowledge of haplotype structure or familial variants can be used to rapidly evaluate an individual at risk for a genetic disease. While ultra-rapid sequencing remains both complex and cost prohibitive, our method is more easily automated than prior approaches and uses smaller volumes of blood, thus may be more easily adopted for future studies of ultra-rapid genome sequencing in the clinical setting. "
Enhancing Neonatal Intensive Care With Rapid Genome Sequencing.
Shan Jiang et al. JAMA Netw Open 2024 2 (2) e240097
(Posted: Feb 27, 2024 9AM)
From the article: "Early diagnosis through genome sequencing can significantly transform clinical care for critically ill neonates. Traditional testing methods often fall short in accurately diagnosing genetic conditions due to overlapping symptoms in this age group. Genome sequencing, on the other hand, has proven more effective and has been used in various contexts for identifying hereditary conditions. A recent study highlights the practicality and benefits of rapid trio genome sequencing (rtGS) in neonatal intensive care units (NICUs) in Israel. "
National Rapid Genome Sequencing in Neonatal Intensive Care.
Daphna Marom et al. JAMA Netw Open 2024 2 (2) e240146
(Posted: Feb 27, 2024 9AM)
From the abstract: "Can rapid trio genome sequencing (rtGS) be deployed in a national public health care setting? In this cohort study that included all neonatal intensive care units in Israel, rtGS in 130 neonates suspected of having a genetic disorder revealed a diagnosis in 50% (12 chromosomal and 52 monogenic disorders and 1 uniparental disomy). Immediate precision medicine was offered for 9% of diagnosed participants, and the mean turnaround time for rapid report was 7 days. These findings suggest that clinical rtGS can be implemented in the neonatal acute care setting in a national public health care system. "
A call for increased inclusivity and global representation in pharmacogenetic testing.
April Kennedy et al. NPJ Genom Med 2024 2 (1) 13
(Posted: Feb 23, 2024 3PM)
From the abstract: "Commercial pharmacogenetic testing panels capture a fraction of the genetic variation underlying medication metabolism and predisposition to adverse reactions. In this study we compared variation in six pharmacogenes detected by whole genome sequencing (WGS) to a targeted commercial panel in a cohort of 308 individuals with family history of pediatric heart disease. In 1% of the cohort, WGS identified rare variants that altered the interpretation of metabolizer status and would thus prevent potential errors in gene-based dosing. "
Ambitious survey of human diversity yields millions of undiscovered genetic variants Analysis of the ‘All of Us’ genomic data set begins to tackle inequities in genetics research.
M Koslov, Nature, February 19, 2024
(Posted: Feb 20, 2024 7AM)
From the abstract: "A massive US programme that aims to improve health care by focusing on the genomes and health profiles of historically underrepresented groups has begun to yield results. Analyses of up to 245,000 genomes gathered by the All of Us programme, run by the US National Institutes of Health in Bethesda, Maryland, have uncovered more than 275 million new genetic markers, nearly 150 of which might contribute to type 2 diabetes. The work has also identified gaps in genetics research on non-white populations. The findings were published on 19 February in a package of papers "
Genomic data in the All of Us Research Program
All of Us, Nature, February 19, 2024
(Posted: Feb 20, 2024 7AM)
From the abstract: "This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1?billion genetic variants, including more than 275?million previously unreported genetic variants, more than 3.9?million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers . "
Non-SARS-CoV-2 respiratory viral detection and whole genome sequencing from COVID-19 rapid antigen test devices: a laboratory evaluation study
MA Moso et al, Lancet Microbe, February 2024
(Posted: Feb 13, 2024 9AM)
From the abstract: " There has been high uptake of rapid antigen test device use for point-of-care COVID-19 diagnosis. Individuals who are symptomatic but test negative on COVID-19 rapid antigen test devices might have a different respiratory viral infection. We aimed to detect and sequence non-SARS-CoV-2 respiratory viruses from rapid antigen test devices, which could assist in the characterisation and surveillance of circulating respiratory viruses in the community."
A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome.
Claude Bhérer et al. NPJ Genom Med 2024 2 (1) 8
(Posted: Feb 09, 2024 10AM)
From the abstract: " Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call “Whole Exome Genome Sequencing” (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed)."
Cost-Effectiveness of Whole-Genome vs Whole-Exome Sequencing Among Children With Suspected Genetic Disorders.
Mario Cesare Nurchis et al. JAMA Netw Open 2024 1 (1) e2353514
(Posted: Jan 30, 2024 8AM)
From the abstract: "Is whole-genome sequencing (WGS) more cost-effective than whole-exome sequencing for children with suspected genetic disorders?
The results of this economic evaluation of a cohort of 870 pediatric patients suggest that adopting WGS as a first-tier strategy would be cost-effective at a willingness-to-pay threshold of €30 000 to €50 000 (US $32?625-$54?375), specifically for the diagnosis of severely ill infants with suspected genetic disorders. ng These findings suggest that wider use of WGS may minimize diagnostic delays and facilitate timely implementation of appropriate treatments. "
Narrowing the Diagnostic Gap: Genomes, Episignatures, Long-Read Sequencing and Health Economic Analyses in an Exome-Negative Intellectual Disability Cohort
KR Dias et al, Genetics in Medicine, January 19, 2024
(Posted: Jan 20, 2024 10AM)
From the abstract: " Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. The ES diagnostic yield was 42/74 (57%). GS diagnoses were made in 9/32 (28%) ES-unresolved families."
Next-generation sequencing and bioinformatics in rare movement disorders.
Michael Zech et al. Nat Rev Neurol 2024 1
(Posted: Jan 15, 2024 10AM)
From the abstract: "In this Perspective, we outline multidimensional strategies for genetic diagnosis in patients with rare movement disorders. We examine bioinformatics tools and computational metrics that have been developed to facilitate accurate prioritization of disease-causing variants. Additionally, we highlight community-driven data-sharing and case-matchmaking platforms, which are designed to foster the discovery of new genotype–phenotype relationships. Finally, we consider how multiomic data integration might optimize diagnostic success by combining genomic, epigenetic, transcriptomic and/or proteomic profiling. "
Landmark national study supports use of whole genome sequencing in standard cancer care
Genomics England, January 2023
(Posted: Jan 14, 2024 10AM)
From the website: "In the largest study of its kind, scientists today report how combining health data with whole genome sequence (WGS) data in patients with cancer can help doctors provide more tailored care for their patients. The research shows that linking WGS data to real-world clinical data can identify changes in cancer DNA that may be relevant for an individual patient’s care, for example by helping identify what treatment might work best for them based on their cancer. "
What Will 2024 Mean for NGS and Genomics?
J Lemieux, GenNew, January 12, 2024
(Posted: Jan 14, 2024 10AM)
From the article: "Recent technological innovations in next-generation sequencing (NGS) have users spoiled for choice. At first, new options began trickling in. But then the floodgates opened in 2022. Folding into this market expansion is the growth in the demand for sequencing, not only from directed genomic sequencing, but also from the growth of other omics technologies such as single-cell genomics and spatial transcriptomics, and of clinical applications such as liquid biopsy—all of which rely on sequencing."
Informed consent for whole genome sequencing in mainstream clinics: logistical constraints and possible solutions
A Chaouch et al, EJHG, January 4, 2024
(Posted: Jan 05, 2024 8AM)
From the article: "The complexity of WGS, the range of possible incidental findings, the inevitable uncertainties, and the often limited understanding about genomics by patients, their family, and sometimes by mainstream clinicians can make informed consent difficult to achieve. Some have argued that an excess of information can be a deterrent for patients, as it may lead to difficulties in ensuring valid consent and hinder access to potentially valuable investigations and treatments. However, it is important that enough information is provided to bring patients’ and families’ hopes and expectations into a realistic alignment with the likely results of WGS. "
Genetic ancestry and diagnostic yield of exome sequencing in a diverse population
Y Mavura et al, NPJ Genomic Medicine, January 3, 2024
(Posted: Jan 03, 2024 8AM)
From the abstract: "It has been suggested that diagnostic yield (DY) from Exome Sequencing (ES) may be lower among patients with non-European ancestries than those with European ancestry. In this empirical study of ES for undiagnosed pediatric and prenatal genetic conditions, genetic ancestry was not associated with the likelihood of a positive diagnosis, supporting the equitable use of ES in diagnosis of previously undiagnosed but potentially Mendelian disorders across all ancestral populations. "
Beyond the exome: utility of long-read whole genome sequencing in exome-negative autosomal recessive diseases
L AlAbdi et al, Genome Medicine, December 14, 2023
(Posted: Dec 15, 2023 8AM)
From the abstract: "Long-read whole genome sequencing (lrWGS) has the potential to address the technical limitations of exome sequencing in ways not possible by short-read WGS. However, its utility in autosomal recessive Mendelian diseases is largely unknown. In a cohort of 34 families in which the suspected autosomal recessive diseases remained undiagnosed by exome sequencing, lrWGS was performed. Likely causal variants were identified in 13 (38%) of the cohort. "
Comprehensive assessment of the genetic characteristics of small for gestational age newborns in NICU: from diagnosis of genetic disorders to prediction of prognosis
H Xiao et al, Genome Medicine, December 13, 2023
(Posted: Dec 13, 2023 7AM)
From the abstract: "Among the 723 SGA newborns, 88(12.2%) received genetic diagnosis, including 42(47.7%) with monogenic diseases and 46(52.3%) with chromosomal abnormalities. SGA with genetic diagnosis showed higher rates in severe SGA(54.5% vs. 41.9%, P=0.0025) than SGA without genetic diagnosis. SGA with chromosomal abnormalities showed higher incidences of physical and neurodevelopmental delay compared to those with monogenic diseases (45.7% vs. 19.0%, P=0.012). "
An expanded genomic database for identifying disease-related variants.
Ryan S Dhindsa et al. Nature 2023 12
(Posted: Dec 07, 2023 8AM)
From the article: " Scientists have long suspected that many disease-causing genetic mutations reside in the 98% of the genome that does not encode proteins, especially in regions that have roles in regulating gene expression. However, it has been challenging to differentiate systematically between harmful and neutral mutations, partly because researchers lack a clear picture of which stretches of the non-coding genome are essential for human health. A recent study addresses this challenge, introducing a tool that analyze large collections of human genomes to identify non-coding regions with greatest potential to cause disease."
Should Secondary Pharmacogenomic Variants Be Actively Screened and Reported When Diagnostic Genome-Wide Sequencing Is Performed in a Child?
Jan M Friedman et al. Genet Med 2023 11 101033
(Posted: Dec 01, 2023 7AM)
From the abstract: "This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. "
Rapid profiling of Plasmodium parasites from genome sequences to assist malaria control.
Jody E Phelan et al. Genome Med 2023 11 (1) 96
(Posted: Nov 11, 2023 3PM)
From the abstract: "Malaria continues to be a major threat to global public health. Whole genome sequencing (WGS) of the underlying Plasmodium parasites has provided insights into the genomic epidemiology of malaria. Genome sequencing is rapidly gaining traction as a diagnostic and surveillance tool for clinical settings, where the profiling of co-infections, identification of imported malaria parasites, and detection of drug resistance are crucial for infection control and disease elimination. To support this informatically, we have developed the Malaria-Profiler tool, which rapidly (within minutes) predicts Plasmodium species, geographical source, and resistance to antimalarial drugs directly from WGS data. "
Rapid genomic testing in critically ill patients with genetic conditions: position statement by the Human Genetics Society of Australasia.
Danya F Vears et al. Eur J Hum Genet 2023 10
(Posted: Oct 23, 2023 8AM)
From the abstract: "Rapid genomic testing in critically ill children is becoming the standard of care where there is a high suspicion of an underlying genetic condition and should be provided equitably for all patients in acute care settings. The HGSA encourages an appropriately resourced multidisciplinary team approach, particularly involving genetic health professionals, wherever practicable in the delivery of rapid genomic testing services. Pre-test genetic counselling should be tailored to the family and followup appointments should be offered. Explicit informed consent for rapid genomic testing should be obtained, even in acute care settings. "
Mobile element insertions in rare diseases: a comparative benchmark and reanalysis of 60,000 exome samples
R Wyngaard et al, EJHG, October 19, 2023
(Posted: Oct 19, 2023 2PM)
From the abstract: "Mobile element insertions (MEIs) are a known cause of genetic disease but have been underexplored due to technical limitations of genetic testing methods. Various bioinformatic tools have been developed to identify MEIs in Next Generation Sequencing data. However, most tools have been developed specifically for genome sequencing (GS) data rather than exome sequencing (ES) data, which remains more widely used for routine diagnostic testing. "
Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test
F Guo et al, Genetics in Medicine, October 12, 2023
(Posted: Oct 13, 2023 1PM)
From the abstract: "Genome sequencing (GS) is one of the most comprehensive assays that interrogate single nucleotide variants, copy number variants, mitochondrial variants, repeat expansions, and structural variants in one assay. Despite the clear technical superiority, the full clinical utility of GS has yet to be determined. The overall diagnostic yield was 28% (585/2100). The diagnostic yield for GS as the first-tier test was 26% (294/1146). Among cases with prior non-diagnostic genetic tests, GS provided a diagnosis for 27% (247/910) of cases. "
Big advocacy, little recognition: the hidden work of Black patients in precision medicine
LH Jerido et al, J Comm Genetics, October 2023
(Posted: Oct 03, 2023 9AM)
From the abstract: " As cost-effective next-generation genome sequencing rapidly develops, calls for greater inclusion of Black people in genomic research, policy, and practice are necessary for effective translation of genomic science into precision population health and medicine. Employing a community-based participatory mixed methods research design, we developed a semi-structured survey that was disseminated to three cancer advocacy organizations."
Knowledge, attitudes and decision regret: a longitudinal survey study of participants offered genome sequencing in the 100,000 Genomes Project
M Peter et al, EJHG, October 3, 2023
(Posted: Oct 03, 2023 9AM)
From the article: "In this study, we used cross-sectional surveys to compare the knowledge, attitudes, and decision regret of 100kGP participants at the time of consenting for GS and at least 12 months later. Like other work in which public attitudes towards GS have been shown to be favorable our study showed that, in general, people felt positively about GS with most reporting it to be beneficial. Notably, we showed that attitudes towards GS remained stable over time, with both positive and negative feelings towards GS remaining unchanged for individuals between T1 and T2."
Viral genetic clustering and transmission dynamics of the 2022 mpox outbreak in Portugal.
Vítor Borges et al. Nat Med 2023 9
(Posted: Sep 12, 2023 7AM)
From the abstract: "Pathogen genome sequencing during epidemics enhances our ability to identify and understand suspected clusters and investigate their relationships. Here, we combine genomic and epidemiological data of the 2022 mpox outbreak to better understand early viral spread, diversification and transmission dynamics. By sequencing 52% of the confirmed cases in Portugal, we identified the mpox virus sublineages with the highest impact on case numbers and fitted them into a global context, finding evidence that several international sublineages probably emerged or spread early."
Genome Sequencing for Newborn Screening—An Effective Approach for Tackling Rare Diseases
S Jiang et al. JAMA Network Open, September 2023
(Posted: Sep 05, 2023 1PM)
From the paper: "Newborn screening is a crucial global public health initiative, with a primary aim to identify congenital disorders that could lead to significant morbidity and mortality if left untreated. However, the scope of traditional newborn screening methods is limited, detecting only a finite number of conditions. With the advent of next-generation genome sequencing technologies, gene panel sequencing as a first-tier newborn screening test is a promising strategy, potentially enabling comprehensive and accurate diagnosis of a broad spectrum of genetic conditions at birth."
A broad genetic test saved one newborn’s life. Research suggests it could help millions of others
L Ungar, AP Health, August 2023
(Posted: Sep 01, 2023 7AM)
From the article: "She nearly died twice when she was a baby, at one point needing emergency surgery for massive bleeding in her brain.
No one knew what was wrong until a test that looked at her full genetic blueprint found a rare bleeding disorder called factor XIII deficiency — an early diagnosis that saved her life. You have this hopeless feeling when you don’t really know what’s going on, said her father. Casting a wide net really made a world of difference figuring this out quickly and getting her the right care that she needed almost immediately.”
Genome sequencing for the fast diagnosis of early-onset epilepsies.
Katrine M Johannesen et al. Lancet Neurol 2023 8 (9) 773-774
(Posted: Aug 23, 2023 10AM)
From the paper: "Technological advances have enabled genetic testing to become the first-line diagnostic investigation for individuals with early-onset epilepsies. A precise genetic diagnosis is essential because it has both personal and clinical utility and might enable timely administration of targeted treatments."
Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study.
Alissa M D'Gama et al. Lancet Neurol 2023 8 (9) 812-825
(Posted: Aug 23, 2023 10AM)
From the abstract: "Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days. For 43 of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days. Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset."
Whole genome sequencing for diagnosis of infants
Genomics Educaton Program, August 18, 2023
(Posted: Aug 18, 2023 8AM)
A 2023 US study has investigated whether panel testing or whole genome sequencing is more rigorous for providing a molecular diagnosis. We consider how the results apply to the NHS and Genomic England’s Newborn Genomes program. The study showed that the panel test returned a diagnosis for 27% of the participants, while WGS provided a diagnosis for 49% of the participants. One of the downsides that the US study found was that it can take longer to receive WGS results compared to panel tests – about six days for WGS compared to four days for panel tests, on average.
Systematic evaluation of genome sequencing for the diagnostic assessment of autism spectrum disorder and fetal structural anomalies
C Lowther et al, AJHG, August 17, 2023
(Posted: Aug 18, 2023 8AM)
Short-read genome sequencing (GS) holds the promise of becoming the primary diagnostic approach for the assessment of autism spectrum disorder (ASD) and fetal structural anomalies (FSAs). However, few studies have comprehensively evaluated its performance against current standard-of-care diagnostic tests: karyotype, chromosomal microarray (CMA), and exome sequencing (ES). Overall, this large-scale evaluation demonstrated that GS significantly outperforms each individual standard-of-care test while also outperforming the combination of all three tests, thus warranting consideration as the first-tier diagnostic approach for the assessment of ASD and FSAs.
We need a genomics-savvy healthcare workforce
Nature Medicine, August 16, 2023
(Posted: Aug 17, 2023 11AM)
The increasingly central role of genomics in healthcare means that not only are more genetic counselors needed, but also multidisciplinary teams are essential for utilizing genomic technologies in the clinical setting. Genomic tests (such as those based on whole-exome or whole-genome sequencing) generate an enormous amount of highly complex data, which requires professionals with specialized bioinformatic skills and the know-how to operate within clinically accredited frameworks. In addition, although genomics is currently the most common ‘-omic’ used in the clinic, transcriptomics and proteomics are also being incorporated into algorithms to inform clinical practice.
Why don’t we all use genomic testing?
A McNeill, EJHG, August 9, 2023
(Posted: Aug 09, 2023 4PM)
Genomic testing is vital for the diagnosis of many rare conditions. However, globally, there is not equity of access to such technologies. Lack of funding is a major barrier. However, Mordaunt et al. found that even when fully funded, uptake of genome sequencing for intellectual disability was less than expected [1]. They suggest that allowing mainstream clinicians to order testing may increase uptake.
Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations
T Hartley et al, GIM, Augiut 5, 2023
(Posted: Aug 07, 2023 9AM)
Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations.
Guidance documents included a broad range of recommendations, but were of low quality, particularly in their rigour of development.
Is there clinical value in screening healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions?
VK Malesu, News Medical, August 2, 2023
(Posted: Aug 04, 2023 9AM)
Is there a clinical value of screening ostensibly healthy newborns and children with genome sequencing in comparison with a gene panel for medically actionable pediatric conditions? In a recent study, genome sequencing uncovered potential pediatric-onset diagnoses in 8.2% of apparently healthy children, with 46.8% of findings associated with high-penetrance conditions. In contrast, only 2.1% of children screened with a panel of 268 genes for medically actionable pediatric conditions were found to be at risk for developing pediatric-onset disease, a significant difference.
Genome-wide mutation profiles from cell-free DNA for early cancer detection
Nature Genetics, July 31, 2023
(Posted: Aug 01, 2023 9AM)
Through whole-genome sequencing of single molecules of circulating cell-free DNA, we found that tumor-derived mutations in cancer genomes are associated with regions of late replication timing and other chromatin features. These genome-wide analyses identified altered regional mutation profiles in people with cancer that distinguished them from people without cancer and reflected tumor burden during therapy.
The landscape of reported VUS in multi-gene panel and genomic testing: Time for a change
HL Rehm et al, Genetics in Medicine, July 30, 2023
(Posted: Jul 31, 2023 11AM)
Variants of uncertain significance (VUS) are a common result of diagnostic genetic testing and can be difficult to manage with potential misinterpretation and downstream costs, including time investment by clinicians. We investigated the rate of VUS reported on diagnostic testing via multi-gene panels (MGPs) and exome and genome sequencing (ES/GS) to measure the magnitude of uncertain results and explore ways to reduce their potentially detrimental impact.
Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients
C. Shroeder et al, EJHG, July 28, 2023
(Posted: Jul 28, 2023 8AM)
We evaluated clinical trio genome sequencing (TGS) in a cohort of 72 pediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n?=?26), neuroblastoma (n?=?15), and nephroblastoma (n?=?10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria.
Rapid Genome Sequencing for Diagnosing Critically Ill Infants and Children: From Evidence to Equitable Implementation
CDC webinar, November 30, 2023
(Posted: Jul 21, 2023 9AM)
Dr. Stephen F. Kingsmore is president/CEO of Rady Children’s Institute for Genomic Medicine (RCIGM), where he leads a multidisciplinary team that is pioneering the use of rapid genome sequencing to diagnose critically ill children, implement precision medicine, and screen for approximately 500 genetic disorders. Dr. Kingsmore holds two Guinness World Records for achieving the fastest molecular diagnosis using whole genome sequencing.
Massive Sequencing Study Leads to High Rate of Diagnosis in Pediatric Genetic Diseases
J Kaltwasser, AJMC, July 2023
(Posted: Jul 17, 2023 8AM)
A new analysis of children with difficult-to-diagnose genetic disorders shows that a genome-driven approach to diagnosis, paired with detailed phenotyping, can significantly improve the likelihood of a diagnosis compared with the previous standard of care.
Genomic Sequencing for Ill Newborns
JAMA Network Learning Podcast July 2023
(Posted: Jul 17, 2023 8AM)
The performance of whole-genome sequencing in comparison with targeted genomic testing methods is not well understood. In this podcast, JAMA Associate Editor W. Gregory Feero, MD, PHD, interviews author Jill L. Maron, MD, MPH, of the Women and Infants Hospital of Rhode Island about a study of whole-genome sequencing vs a commercially available targeted genetic testing platform for diagnosing ill neonates with suspected genetic conditions.
A new study of sick infants sees potential in DNA sequencing, but also a need for better ways to interpret the genome
J Wosen, Stat News, July 11, 2023
(Posted: Jul 12, 2023 9AM)
here’s growing evidence that DNA sequencing can help diagnose the health care system’s youngest patients — babies in their first year of life. But a new report resurfaces a thorny challenge in researchers’ quest to turn long strings of A’s, T’s, G’s, and C’s into information doctors and patients can use: Reading the genome is one challenge, interpreting it is another.
Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder
JL Marone et al, JAMA, July 11, 2023
(Posted: Jul 11, 2023 0PM)
How does molecular diagnostic yield and the time to return of results differ between genomic sequencing and a commercially available targeted neonatal gene-sequencing test in 400 hospitalized infants suspected of having a genetic disorder? Median time to result was 6.1 days for genomic sequencing and 4.2 days for the targeted gene-sequencing test. Molecular diagnostic yield of genomic sequencing was 49% (95% CI, 44%-54%) vs 27% (95% CI 23%-32%) with the targeted gene-sequencing test. Changes in clinical interventions affected 19% of participants.
Implementation of Rapid Genome Sequencing for Critically Ill Infants With Complex Congenital Heart Disease.
Thomas Hays et al. Circ Genom Precis Med 2023 7 e004050
(Posted: Jul 10, 2023 8AM)
We conducted a prospective evaluation of rGS to improve the care of infants with complex CHD in our cardiac neonatal intensive care unit. In a cohort of 48 infants with complex CHD, rGS diagnosed 14 genetic disorders in 13 (27%) individuals and led to changes in clinical management in 8 (62%) cases with diagnostic results. These included 2 cases in whom genetic diagnoses helped avert intensive, futile interventions before cardiac neonatal intensive care unit discharge, and 3 cases in whom eye disease was diagnosed and treated in early childhood.
Provision and Availability of Genomic Medicine Services in Level IV Neonatal Intensive Care Units
MH Wojcik et al, Genet Med, July 6, 2023
(Posted: Jul 07, 2023 9AM)
We developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children's Hospitals Neonatal Consortium (CHNC), requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. Overall response rate was 74% (32/43). While chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites),
ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG)
DT Miller et al, Genetics in Medicine, June 22, 2023
(Posted: Jun 22, 2023 7AM)
The American College of Medical Genetics and Genomics (ACMG) previously published guidance for reporting secondary findings (SFs) in the context of clinical exome and genome sequencing. The ACMG Secondary Findings Working Group (SFWG) and Board of Directors (BODs) have agreed that the list of recommended genes should now be updated annually, but with an ongoing goal of maintaining this as a minimum list. Reporting of SFs should be considered neither a replacement for indication-based diagnostic clinical genetic testing nor a form of population screening.
Parents’ Perspectives on the Utility of Genomic Sequencing in the Neonatal Intensive Care Unit
AA Lemke et al, JMP, June 21, 2023
(Posted: Jun 21, 2023 7AM)
Key themes included that (1) GS in infancy is important for reproductive decision making, preparing for the child’s future care, ending the diagnostic odyssey, and sharing results with care providers; (2) the timing of disclosure was acceptable for most parents, although many reported the NICU environment was overwhelming; and (3) parents deny that receiving GS results during infancy exacerbated parent–infant bonding, and reported variable impact on their feelings of guilt.
Applications of long-read sequencing to Mendelian genetics.
Francesco Kumara Mastrorosa et al. Genome Med 2023 6 (1) 42
(Posted: Jun 20, 2023 7AM)
Long-read sequencing (LRS) is a promising technology for both increasing the solve rate and decreasing the amount of time required to make a precise genetic diagnosis. Here, we summarize current LRS technologies, give examples of how they have been used to evaluate complex genetic variation and identify missing variants, and discuss future clinical applications of LRS. As costs continue to decrease, LRS will find additional utility in the clinical space.
Clinical genome sequencing: three years’ experience at a tertiary children’s hospital
RD Kumar et al, Genetics in Medicine, June 15, 2023
(Posted: Jun 16, 2023 1PM)
We retrospectively reviewed GS orders for admitted patients for a nearly 3-year period from March 2020 through December 2022. We gathered anonymized clinical data from the electronic health record to answer the study questions. The diagnostic yield over 97 admitted patients was 35%. The majority of GS clinical indications were neurologic or metabolic (61%) and most patients were in intensive care (58%).
Recommendations for Next-Generation Sequencing Germline Variant Confirmation: A Joint Report of the Association for Molecular Pathology and National Society of Genetic Counselors.
Kristy R Crooks et al. J Mol Diagn 2023 5
(Posted: Jun 09, 2023 8AM)
On the basis of the results of a survey of the literature, a survey of laboratory practices, and subject expert matter consensus, eight recommendations are presented, providing a common framework for clinical laboratory professionals to develop or refine individualized laboratory policies and procedures regarding orthogonal confirmation of germline variants detected by NGS.
Integrated multi-omics for rapid rare disease diagnosis on a national scale.
Sebastian Lunke et al. Nat Med 2023 6
(Posted: Jun 09, 2023 8AM)
Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9?d and diagnostic yield was 47%.
Genomic Sequencing: A Decade to a Day
Genomics Education UK, June 2, 2023
(Posted: Jun 04, 2023 2PM)
Curiosity, patience, and the humble pea plant are three fundamental factors that have allowed us to sequence an entire human genome in 24 hours
The impact that the exponential growth of technology has had on genomics in the last twenty years is dizzying. But how did we get here today? It’s worth taking a quick break from the here and now to consider the path paved by numerous scientists over the last 150 years that has brought us to a point in history where genome sequencing is revolutionizing healthcare.
Pathogen genomics in public health laboratories: successes, challenges, and lessons learned from California's SARS-CoV-2 Whole-Genome Sequencing Initiative, California COVIDNet.
Emily A Smith et al. Microb Genom 2023 6 (6)
(Posted: Jun 04, 2023 2PM)
The California Department of Public Health, in partnership with Theiagen Genomics, was an early adopter of cloud-based resources for bioinformatics and genomic epidemiology, resulting in the creation of a SARS-CoV-2 genomic surveillance system that combined the efforts of more than 40 sequencing laboratories across government, academia and industry to form California COVIDNet, California's SARS-CoV-2 Whole-Genome Sequencing Initiative. Open-source bioinformatics workflows, ongoing training sessions for the public health workforce, and automated data transfer to visualization tools all contributed to the success of California COVIDNet.
Estimating clinical risk in gene regions from population sequencing cohort data.
James D Fife et al. Am J Hum Genet 2023 5
(Posted: Jun 02, 2023 9AM)
While pathogenic variants can significantly increase disease risk, it is still challenging to estimate the clinical impact of rare missense variants more generally. Even in genes such as BRCA2 or PALB2, large cohort studies find no significant association between breast cancer and rare missense variants collectively. Here, we introduce REGatta, a method to estimate clinical risk from variants in smaller segments of individual genes.
Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population
A Slavotinek et al, NPJ Genomic Medicine, May 26, 2023
(Posted: May 27, 2023 7AM)
We identified definitive positive or probable positive results in 201/845 (23.8%) patients, with a significantly higher diagnostic rate in pediatric (26.7%) compared to prenatal patients (19.0%) (P?=?0.01). For both pediatric and prenatal patients, the diagnostic yield and frequency of inconclusive findings did not differ significantly between URM and non-URM patients or between patients with US status and those without US status.
GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19
EP Castineira et al, Nature, May 17, 2023
(Posted: May 17, 2023 0PM)
Here we analyze 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously.
Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations
C Ching et al, Genetics in Medicine, May 13, 2023
(Posted: May 14, 2023 9AM)
This meta-analysis aims to compare the diagnostic and clinical utility of whole-exome sequencing (WES) versus whole-genome sequencing (WGS) in pediatric and adult patients with rare diseases across diverse populations. One-hundred-and-sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of WES (0.38, 95% CI 0.36-0.40) and WGS (0.34, 95% CI 0.30-0.38) were similar.
Perspectives of Rare Disease Experts on Newborn Genome Sequencing.
Nina B Gold et al. JAMA Netw Open 2023 5 (5) e2312231
(Posted: May 09, 2023 5AM)
Do rare disease experts endorse genome sequencing of newborns to screen for treatable genetic diseases, and do they agree on which genes to include?
In this survey study of 238 rare disease experts, 87.9% agreed that genomic sequencing for monogenic treatable conditions should be available to all newborns. A total of 42 gene-disease pairs were endorsed by more than 80% of the experts. In this study, rare disease experts broadly endorsed screening of newborns with genome sequencing, and there was substantial concordance on a limited number of specific gene-disease pairs for prioritization.
Molecular diagnostic yield of genome sequencing versus targeted gene panel testing in racially and ethnically diverse pediatric patients
NA Husn et al, Genetics in Medicine, May 6, 2023
(Posted: May 06, 2023 7AM)
Adoption of genome sequencing (GS) as a first-line test requires evaluation of its diagnostic yield. We evaluated the GS and targeted gene panel (TGP) testing in diverse pediatric patients (probands) with suspected genetic conditions. 645 probands (median age 9 years) underwent genetic testing, and 113 (17.5%) received a molecular diagnosis. Among 642 probands with both GS and TGP testing, GS yielded 106 (16.5%) and TGPs yielded 52 (8.1%) diagnoses (P < .001). Yield was greater for GS vs. TGPs in Hispanic/Latino(a) (17.2% vs. 9.5%, P < .001) and White/European American (19.8% vs. 7.9%, P < .001), but not in Black/African American (11.5% vs. 7.7%, P = .22) population groups.
Variant calling and benchmarking in an era of complete human genome sequences.
Nathan D Olson et al. Nat Rev Genet 2023 4
(Posted: Apr 19, 2023 7AM)
We describe how advances in long reads, deep learning, de novo assembly and pangenomes have expanded access to variant calls in increasingly challenging, repetitive genomic regions, including medically relevant regions, and how new benchmark sets and benchmarking methods illuminate their strengths and limitations. Finally, we explore the possible future of more complete characterization of human genome variation in light of the recent completion of a telomere-to-telomere human genome reference assembly.
Why genetic testing should always be offered to children with neurodevelopmental differences
D Ondrasick, Stat News, April 10., 2023
(Posted: Apr 11, 2023 0PM)
As a board-certified pediatrician and the mother of a child with a rare disease, I believe the medical system is failing the rare disease community by vastly underdiagnosing genetic disorders. Most families are offered either no genetic testing at all or only limited panels that cannot find most genetic mutations. Given the benefits I have seen for my family and my patients, I urge the AAP to develop new guidelines that are aligned with the 2021 American College of Medical Genetics and Genomics practice guidelines. These recommend whole exome/genome sequencing as a first or second-tier test for pediatric patients with congenital anomalies, developmental delay, or intellectual disability.
Comparison of Genetic Profiles of Neonates in Intensive Care Units Conceived With or Without Assisted Reproductive Technology
Z Huang et al, JAMA Network Open, April 4, 2023
(Posted: Apr 04, 2023 0PM)
Are molecular defects more common in newborns in the neonatal intensive care unit (NICU) conceived by assisted reproductive technology (ART) than in naturally conceived neonates? In this cross-sectional analysis of infants in NICUs for whom genetic analysis was completed, there was no significant difference in diagnoses of genetic conditions between those conceived with ART and those conceived unassisted (10.1% vs 13.2%). The proportion of de novo variants was also not significantly different.
Design and Implementation of a National SARS-CoV-2 Monitoring Program in England: REACT-1 Study.
Paul Elliott et al. American journal of public health 2023 3 e1-e10
(Posted: Mar 30, 2023 8AM)
The REal-time Assessment of Community Transmission-1 (REACT-1) Study was funded by the Department of Health and Social Care in England to provide reliable and timely estimates of prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection over time, by person and place.
The study provided inter alia real-time data on SARS-CoV-2 prevalence over time, by area, and by sociodemographic variables; estimates of vaccine effectiveness; and symptom profiles, and detected emergence of new variants based on viral genome sequencing.
Mathematical modeling of neuroblastoma associates evolutionary patterns with outcomes
G Caravagna, Nature Genetics, March 27, 2023
(Posted: Mar 29, 2023 9AM)
A new study deciphers the origin and evolution of childhood neuroblastoma using genome sequencing data, mathematical models and statistical inference, showing how neuroblastoma evolution is an accurate predictor of outcome.
Newborn genome screening in the USA: early steps on a challenging path
B Furlough, Lancet Child & Adol Health, , April 2023
(Posted: Mar 22, 2023 7AM)
As of March, 2023, the Genomic Uniform-screening Against Rare Diseases In All Newborns (GUARDIAN) study at Columbia University and New York-Presbyterian hospitals in New York, NY, USA, has enrolled more than 1000 of a planned 100?000 babies who will undergo whole-genome sequencing over the next 4 years to detect gene variants associated with 158 rare diseases. It will be the largest US study to date of genome sequencing at birth to detect rare genetic diseases.
Automated prioritization of sick newborns for whole genome sequencing using clinical natural language processing and machine learning.
Bennet Peterson et al. Genome medicine 2023 3 (1) 18
(Posted: Mar 20, 2023 7AM)
We have developed automated means to prioritize patients for rapid and whole genome sequencing (rWGS and WGS) directly from clinical notes. Our approach combines a clinical natural language processing (CNLP) workflow with a machine learning-based prioritization tool named Mendelian Phenotype Search Engine (MPSE). MPSE accurately and robustly identified NICU patients selected for WGS by clinical experts from Rady Children’s Hospital in San Diego (AUC 0.86) and the University of Utah (AUC 0.85).
The genetic revolution transforming kidney disease.
Bianca Nogrady et al. Nature 2023 3 (7951) S14-S15
(Posted: Mar 20, 2023 7AM)
Once a tool only for research, genome sequencing is now being used by clinicians to identify the cause of chronic kidney disease (CKD), to guide treatment, advise family members and provide reproductive genetic counselling. It’s also being used to screen people with suspected kidney disease or even the general population, allowing physicians to intervene earlier in the course of the disease and delay — or even avoid — the worst outcomes.
Diagnostic Yield of Exome Sequencing in Cerebral Palsy and Implications for Genetic Testing Guidelines: A Systematic Review and Meta-analysis.
Pedro J Gonzalez-Mantilla et al. JAMA pediatrics 2023 3
(Posted: Mar 07, 2023 6PM)
Is the diagnostic yield of exome or genome sequencing in cerebral palsy similar to that of other neurodevelopmental disorders for which exome sequencing is recommended as a first-tier clinical diagnostic test? In this systematic review and meta-analysis that included 13 studies and 2612 individuals with cerebral palsy, the diagnostic yield of exome or genome sequencing was 31.1%, which is similar to that of other neurodevelopmental disorders, regardless of comorbid intellectual disability/developmental delay.
Diagnostics for rare diseases
Q's and A's with S Kingsmore, Comm Medicine, February 28, 2023
(Posted: Feb 28, 2023 7AM)
What are the best approaches currently for diagnosis of rare diseases? Whole genome sequencing is, in the immortal words of JRR Tolkein, the “One ring to rule them all, one ring to find them, One ring to bring them all”. By decoding the entire genome it’s possible to examine it for variants responsible for almost all 7300 genetic diseases (and often to rule them out as causes of a child’s illness).
Combined low-pass whole genome and targeted sequencing in liquid biopsies for pediatric solid tumors
E Chistodoulou et al, NPJ Precision Oncology, February 20, 2023
(Posted: Feb 20, 2023 8AM)
We designed a liquid biopsy (LB) platform employing low-pass whole genome sequencing (LP-WGS) and targeted sequencing of cell-free (cf) DNA from plasma to detect genome-wide copy number alterations (CNAs) and gene fusions in pediatric solid tumors. A total of 143 plasma samples were analyzed from 19 controls and 73 patients, including 44 bone or soft-tissue sarcomas and 12 renal, 10 germ cell, five hepatic, and two thyroid tumors. cfDNA was isolated from plasma collected at diagnosis, during and after therapy, and/or at relapse.
A systematic review of economic evaluations of whole-genome sequencing for the surveillance of bacterial pathogens.
Vivien Price et al. Microbial genomics 2023 2 (2)
(Posted: Feb 17, 2023 9AM)
Six hundred and eighty-one articles were identified, of which 49 proceeded to full-text screening, with 9 selected for inclusion. All had been published since 2019. Heterogeneity was high. Five studies assessed WGS for hospital surveillance and four analyzed foodborne pathogens. Four were cost-benefit analyses, one was a cost-utility analysis, one was a cost-effectiveness analysis, one was a combined cost-effectiveness and cost-utility analysis, one combined cost-effectiveness and cost-benefit analyses and one was a partial analysis. All studies supported the use of WGS as a surveillance tool on economic grounds.
Scalable, high quality, whole genome sequencing from archived, newborn, dried blood spots
Y Ding et al, NPJ Genomic Medicine, February 14, 2023
(Posted: Feb 14, 2023 7AM)
We describe simple methods for gDNA extraction and WGS library preparation from several types of DBS. We tested these methods in DBS from 25 individuals who had previously undergone diagnostic, clinical WGS and 29 randomly selected DBS cards collected for NBS from the California State Biobank. While gDNA from DBS had significantly less yield than from EDTA blood from the same individuals, it was of sufficient quality and quantity for WGS without PCR.
Reclassification of the Etiology of Infant Mortality With Whole-Genome Sequencing.
Mallory J Owen et al. JAMA network open 2023 2 (2) e2254069
(Posted: Feb 11, 2023 8AM)
What proportion of infant mortality is explained by genetic diseases? In this cohort study of 112 infant deaths, single-locus genetic diseases were the most common antecedent of infant mortality (41%). Treatments positively associated with outcomes were available for 30% of these genetic diseases.
The study results suggest that because treatable genetic diseases are associated with considerable infant mortality, strategies for neonatal diagnosis may be associated with decreased infant mortality.
Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children.
Danyel Lee et al. Science (New York, N.Y.) 2022 12 (6632) eabo3627
(Posted: Feb 11, 2023 8AM)
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects one in 10,000 infected children. MIS-C is reminiscent of Kawasaki disease and its etiology remains unknown. Lee et al. performed whole-exome and whole-genome sequencing on a cohort of MIS-C patients and uncovered autosomal-recessive deficiencies of OAS1, OAS2, or RNASEL in around 1% of the cohort. These genes are components of a signaling pathway that suppresses inflammation in double-stranded RNA–stimulated mononuclear phagocytes.
The value of exomes across the ages
A McNeil, EJHG, February 3, 2023
(Posted: Feb 04, 2023 7AM)
Utility of long-read sequencing for All of Us
M Mahmoud et a, BIORXIV, January 24, 2023
(Posted: Jan 26, 2023 6AM)
We compared the performance of traditional short-read sequencing with long-read sequencing in a small cohort of samples from the HapMap project and two AoU control samples representing eight datasets. Our analysis revealed substantial differences in the ability of these technologies to accurately sequence complex medically relevant genes, particularly in terms of gene coverage and pathogenic variant identification. Our results show that HiFi reads produced the most accurate results for both small and large variants.
A Solve-RD ClinVar-based reanalysis of 1,522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing.
Denommé-Pichon Anne-Sophie et al. Genetics in medicine : official journal of the American College of Medical Genetics 2023 1 100018
(Posted: Jan 22, 2023 8AM)
A one-year genomic investigation of Escherichia coli epidemiology and nosocomial spread at a large US healthcare network
EG Mills et al, Genome Medicine, December 30, 2022
(Posted: Dec 31, 2022 7AM)
Whole-genome sequencing (WGS), phylogenetic analysis, and antibiotic susceptibility testing were performed for a complete set of 2075 E. coli clinical isolates collected from 1776 patients at a large tertiary healthcare network in the USA between October 2019 and September 2020. The study provides a rare and contemporary survey on the epidemiology and spread of E. coli in a large US healthcare network. While surveillance and infection control efforts often focus on ESBL and MDR lineages, our findings reveal that non-MDR isolates represent a large burden of infections, including those of predicted nosocomial origins.
Parents’ decision-making regarding whether to receive adult-onset only genetic findings for their children: Findings from the BabySeq Project
S Pereira et al, Genetics in Medicine, December 20, 2022
(Posted: Dec 20, 2022 8AM)
Parents noted several motivations to receive and reasons to decline adult-onset only results. Most commonly, parents cited early intervention/surveillance (n=11), implications for family heath (n=7), and the ability to prepare (n=6) as motivations to receive these results. The most common reasons to decline were protection of the child’s future autonomy (n=4), negative impact on parenting (n=3), and anxiety about future disease (n=3).
RNA Sequencing as a Diagnostic Tool.
Ketkar Shamika et al. JAMA 2022 12
(Posted: Dec 20, 2022 8AM)
RNA sequencing (RNA-seq) is a new tool in the genetic diagnostic laboratory made possible by the advent of low-cost, high-throughput, next-generation sequencing technology. Historically, RNA studies were limited to gene expression using microarray technology for the detection of gene rearrangements and quantification of gene expression for predefined genes. RNA-seq allows detection of qualitative and quantitative changes in RNA expression across the genome in clinical samples and is increasingly being used as an adjunct to diagnostic exome sequencing and whole-genome sequencing.
Digital PCR discriminates between SARS-CoV-2 Omicron variants and immune escape mutations
SC Holland et al, MEDRXIV, December 19, 2022
(Posted: Dec 20, 2022 7AM)
We demonstrate their validity on 596 clinical saliva specimens that were sequence-verified using Illumina whole genome sequencing. Next, we developed dPCR assays for spike mutations R346T, K444T, N460K, F486V, and F486S mutations that are associated with host immune evasion and reduced therapeutic monoclonal antibody efficacy. We demonstrate that these assays can be run individually or multiplexed to detect the presence of up to 4 SNPs in a single assay.
COVID spurs boom in genome sequencing for infectious diseases
S Mallapaty, Nature, December 15, 2022
(Posted: Dec 15, 2022 8AM)
From Dengue to Ebola, laboratories in Asia and Africa are using sequencing technology and skills acquired during the pandemic to quickly track endemic diseases. Before the pandemic, genomic sequencing was mainly reserved for research in many regions, but now it is being used for public health.
As testing for SARS-CoV-2 declines in many regions, countries are starting to pivot to sequencing endemic pathogens. This increased interest in sequencing is generating more data for research, and opportunities to collaborate on new treatments and vaccines, say researchers. But there is a shortage of people who can interpret sequencing data such as bioinformaticians and epidemiologists,
Points to consider in the detection of germline structural variants using next-generation sequencing: A statement of the American College of Medical Genetics and Genomics (ACMG)
G Raca et al, Genetics in Medicine, December 12, 2022
(Posted: Dec 12, 2022 9AM)
Although technically feasible, simultaneously testing for a wide range of genomic alterations (including potentially single-nucleotide variants [SNVs], indels, CNVs, BCRs, regions of homozygosity [ROHs], mitochondrial variants, and repeat expansions [REs]) is a complex task, which may present clinical laboratories with unanticipated technical and interpretive challenges. In addition, the availability of a single test for a variety of variant types introduces a new dilemma for clinicians regarding how to best incorporate this type of comprehensive testing into the diagnostic workup of a patient.
Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing
LJ Hocking et al, EJHG, December 6, 2022
(Posted: Dec 06, 2022 0PM)
We sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes.
Gradual emergence followed by exponential spread of the SARS-CoV-2 Omicron variant in Africa.
Fischer Carlo et al. Science (New York, N.Y.) 2022 12 eadd8737
(Posted: Dec 03, 2022 6AM)
The geographic and evolutionary origins of the SARS-CoV-2 Omicron variant (BA.1), which was first detected mid-November 2021 in Southern Africa, remain unknown. We tested 13,097 COVID-19 patients sampled between mid-2021 to early 2022 from 22 African countries for BA.1 by real-time RT-PCR. By November-December 2021, BA.1 had replaced the Delta variant in all African sub-regions following a South-North gradient, with a peak Rt of 4.1. Polymerase chain reaction and near-full genome sequencing data revealed genetically diverse Omicron ancestors already existed across Africa by August 2021.
The genomic and immune landscape of long-term survivors of high-grade serous ovarian cancer.
Garsed Dale W et al. Nature genetics 2022 12
(Posted: Dec 02, 2022 6AM)
We analyzed 60 patients with advanced-stage HGSC who survived more than 10 years after diagnosis using whole-genome sequencing, transcriptome and methylome profiling of their primary tumor samples, comparing this data to 66 short- or moderate-term survivors. Tumors of long-term survivors were more likely to have multiple alterations in genes associated with DNA repair and more frequent somatic variants resulting in an increased predicted neoantigen load.
