scholarly journals Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 205
Author(s):  
Gaber Bergant ◽  
Aleš Maver ◽  
Borut Peterlin
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Diagnostic Testing ◽  
Positive Family History ◽  
Clinical Diagnostics ◽  
Whole Genome ◽  
Exon Duplication ◽  
The Impact

Several patients with rare genetic disorders remain undiagnosed following comprehensive diagnostic testing using whole-exome sequencing (WES). In these patients, pathogenic genetic variants may reside in intronic or regulatory regions or they may emerge through mutational mechanisms not detected by WES. For this reason, we implemented whole-genome sequencing (WGS) in routine clinical diagnostics of patients with undiagnosed genetic disorders and report on the outcome in 30 patients. Criteria for consideration included (1) negative WES, (2) a high likelihood of a genetic cause for the disorders, (3) positive family history, (4) detection of large blocks of homozygosity or (5) detection of a single pathogenic variant in a gene associated with recessive conditions. We successfully discovered a causative genetic variant in 6 cases, a retrotranspositional event in the APC gene, non-coding variants in the intronic region of the OTC gene and the promotor region of the UFM1 gene, repeat expansion in the RFC1 gene and a single exon duplication in the CNGB3 gene. We also discovered one coding variant, an indel, which was missed by variant caller during WES data analysis. Our study demonstrates the impact of WGS in the group of patients with undiagnosed genetic diseases after WES in the clinical setting and the diversity of mutational mechanisms discovered, which would remain undetected using other methods.

scholarly journals Whole-genome sequencing from the New Zealand Saccharomyces cerevisiae population reveals the genomic impacts of novel microbial range expansion

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Peter Higgins ◽  
Cooper A Grace ◽  
Soon A Lee ◽  
Matthew R Goddard
Keyword(s):  
Saccharomyces Cerevisiae ◽  
New Zealand ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Range Expansion ◽  
Copy Number ◽  
Small Scale ◽  
Whole Genome ◽  
Copy Number Changes ◽  
The Impact

Abstract Saccharomyces cerevisiae is extensively utilized for commercial fermentation, and is also an important biological model; however, its ecology has only recently begun to be understood. Through the use of whole-genome sequencing, the species has been characterized into a number of distinct subpopulations, defined by geographical ranges and industrial uses. Here, the whole-genome sequences of 104 New Zealand (NZ) S. cerevisiae strains, including 52 novel genomes, are analyzed alongside 450 published sequences derived from various global locations. The impact of S. cerevisiae novel range expansion into NZ was investigated and these analyses reveal the positioning of NZ strains as a subgroup to the predominantly European/wine clade. A number of genomic differences with the European group correlate with range expansion into NZ, including 18 highly enriched single-nucleotide polymorphism (SNPs) and novel Ty1/2 insertions. While it is not possible to categorically determine if any genetic differences are due to stochastic process or the operations of natural selection, we suggest that the observation of NZ-specific copy number increases of four sugar transporter genes in the HXT family may reasonably represent an adaptation in the NZ S. cerevisiae subpopulation, and this correlates with the observations of copy number changes during adaptation in small-scale experimental evolution studies.

scholarly journals Piglet Gut and in-Barn Manure from Farms on a Raised without Antibiotics Program Display Reduced Antimicrobial Resistance but an Increased Prevalence of Pathogens

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1152
Author(s):  
Samuel M. Chekabab ◽  
John R. Lawrence ◽  
Alvin C. Alvarado ◽  
Bernardo Z. Predicala ◽  
Darren R. Korber
Keyword(s):  
Antimicrobial Resistance ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Fecal Samples ◽  
Time Points ◽  
Conventional Farms ◽  
Production Practices ◽  
On Farm ◽  
The Impact

In response to new stringent regulations in Canada regarding the use of antibiotics in animal production, many farms have implemented practices to produce animals that are raised without antibiotics (RWA) from birth to slaughter. This study aims to assess the impact of RWA production practices on reducing the actual total on-farm use of antibiotics, the occurrence of pathogens, and the prevalence of antimicrobial resistance (AMR). A 28-month longitudinal surveillance of farms that adopted the RWA program and conventional farms using antibiotics in accordance with the new regulations (non-RWA) was conducted by collecting fecal samples from 6-week-old pigs and composite manure from the barn over six time points and applying whole-genome sequencing (WGS) to assess the prevalence of AMR genes as well as the abundance of pathogens. Analysis of in-barn drug use records confirmed the decreased consumption of antibiotics in RWA barns compared to non-RWA barns. WGS analyses revealed that RWA barns had reduced the frequency of AMR genes in piglet feces and in-barn manure. However, metagenomic analyses showed that RWA barns had a significant increase in the frequency of pathogenic Firmicutes in fecal samples and pathogenic Proteobacteria in barn manure samples.

scholarly journals Evaluation of whole genome sequencing for the identification and typing of Vibrio cholerae

2018 ◽  
Author(s):  
David R. Greig ◽  
Ulf Schafer ◽  
Sophie Octavia ◽  
Ebony Hunter ◽  
Marie A. Chattaway ◽  
...  
Keyword(s):  
Public Health ◽  
Whole Genome Sequencing ◽  
Vibrio Cholerae ◽  
Species Identification ◽  
Genome Sequencing ◽  
National Level ◽  
Whole Genome ◽  
Surveillance Programs ◽  
El Tor ◽  
The Impact

AbstractEpidemiological and microbiological data on Vibrio cholerae isolated between 2004 and 2017 (n=836) and held in the Public Health England culture archive were reviewed. The traditional biochemical species identification and serological typing results were compared with the genome derived species identification and serotype for a sub-set of isolates (n=152). Of the 836 isolates, 750 (89.7%) were from faecal specimens, 206 (24.6%) belonged to serogroup O1 and seven (0.8%) were serogroup O139, and 792 (94.7%) isolates from patients reporting recent travel abroad, most commonly to India (n=209) and Pakistan (n=104). Of the 152 isolates of V. cholerae speciated by kmer identification, 149 (98.1%) were concordant with the traditional biochemical approach. Traditional serotyping results were 100% concordant with the whole genome sequencing (WGS) analysis for identification of serogroups O1 and O139 and Classical and El Tor biotypes. ctxA was detected in all isolates of V. cholerae O1 El Tor and O139 belonging to sequence type (ST) 69, and in V. cholerae O1 Classical variants belonging to ST73. A phylogeny of isolates belonging to ST69 from UK travellers clustered geographically, with isolates from India and Pakistan located on separate branches. Moving forward, WGS data from UK travellers will contribute to global surveillance programs, and the monitoring of emerging threats to public health and the global dissemination of pathogenic lineages. At the national level, these WGS data will inform the timely reinforcement of direct public health messaging to travellers and mitigate the impact of imported infections and the associated risks to public health.

scholarly journals Evaluation of Whole-Genome Sequencing for Identification and Typing of Vibrio cholerae

2018 ◽  
Vol 56 (11) ◽  
Author(s):  
David R. Greig ◽  
Ulf Schaefer ◽  
Sophie Octavia ◽  
Ebony Hunter ◽  
Marie A. Chattaway ◽  
...  
Keyword(s):  
Public Health ◽  
Whole Genome Sequencing ◽  
Vibrio Cholerae ◽  
Species Identification ◽  
Genome Sequencing ◽  
National Level ◽  
Whole Genome ◽  
Content Type ◽  
El Tor ◽  
The Impact

ABSTRACT Epidemiological and microbiological data on Vibrio cholerae strains isolated between April 2004 and March 2018 (n = 836) and held at the Public Health England culture archive were reviewed. The traditional biochemical species identification and serological typing results were compared with the genome-derived species identification and serotype for a subset of isolates (n = 152). Of the 836 isolates, 750 (89.7%) were from a fecal specimen, 206 (24.6%) belonged to serogroup O1, and 7 (0.8%) were serogroup O139; 792 (94.7%) isolates were from patients reporting recent travel abroad, most commonly to India (n = 209) and Pakistan (n = 104). Of the 152 V. cholerae isolates identified by use of kmer, 149 (98.1%) were concordant with those identified using the traditional biochemical approach. Traditional serotyping results were 100% concordant with those of the whole-genome sequencing (WGS) analysis for the identification of serogroups O1 and O139 and classical and El Tor biotypes. ctxA was detected in all isolates of V. cholerae O1 El Tor and O139 belonging to sequence type 69 (ST69) and in V. cholerae O1 classical variants belonging to ST73. A phylogeny of isolates belonging to ST69 from U.K. travelers clustered geographically, with isolates from India and Pakistan located on separate branches. Moving forward, WGS data from U.K. travelers will contribute to global surveillance programs and the monitoring of emerging threats to public health and the global dissemination of pathogenic lineages. At the national level, these WGS data will inform the timely reinforcement of direct public health messaging to travelers and mitigate the impact of imported infections and the associated risks to public health.

Genetics of neuropsychiatric disease

2020 ◽  
pp. 127-140
Author(s):  
Stefania Bruno ◽  
Nayana Lahiri
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Disorders ◽  
Single Gene ◽  
Diagnostic Techniques ◽  
Genetic Influences ◽  
Whole Genome ◽  
Neuropsychiatric Disease ◽  
Genomic Technologies ◽  
Whole Exome

To better understand the intricacies of genetic influences on neuropsychiatric disease, it is important first to have a grounding in the models of human inheritance and current diagnostic techniques. This chapter covers the fundamentals of genetic disorders, giving insights into chromosomal, single-gene, and mitochondrial disorders. Moreover, it explores the changing applications of genomic technologies, such as whole exome and whole genome sequencing, through the lens of their implications for neuropsychiatry. Clinical examples are provided to give an idea of the genetic underpinnings of Alzheimer’s disease, Parkinson’s disease, and other familiar disorders.

scholarly journals Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Christian R. Marshall ◽  
◽  
Shimul Chowdhury ◽  
Ryan J. Taft ◽  
Mathew S. Lebo ◽  
...  
Keyword(s):  
Best Practices ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Test Performance ◽  
Genetic Disorders ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Whole Genome ◽  
Analytical Validation ◽  
Whole Exome

Abstract Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders; however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading healthcare and research organizations in the US and Canada, was formed to expand access to high-quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders, and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice, and support safe and effective WGS testing for diagnosis of germline disease.

scholarly journals Whole Genome Sequencing of A(H3N2) Influenza Viruses Reveals Variants Associated with Severity during the 2016–2017 Season

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 108 ◽  
Author(s):  
Bruno Simon ◽  
Maxime Pichon ◽  
Martine Valette ◽  
Gwendolyne Burfin ◽  
Mathilde Richard ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Influenza Viruses ◽  
Influenza Surveillance ◽  
Whole Genome ◽  
University Hospitals ◽  
Surveillance Network ◽  
Genetic Traits ◽  
H3n2 Influenza ◽  
The Impact

Influenza viruses cause a remarkable disease burden and significant morbidity and mortality worldwide, and these impacts vary between seasons. To understand the mechanisms associated with these differences, a comprehensive approach is needed to characterize the impact of influenza genomic traits on the burden of disease. During 2016–2017, a year with severe A(H3N2), we sequenced 176 A(H3N2) influenza genomes using next generation sequencing (NGS) for routine surveillance of circulating influenza viruses collected via the French national influenza community-based surveillance network or from patients hospitalized in the intensive care units of the University Hospitals of Lyon, France. Taking into account confounding factors, sequencing and clinical data were used to identify genomic variants and quasispecies associated with influenza severity or vaccine failure. Several amino acid substitutions significantly associated with clinical traits were found, including NA V263I and NS1 K196E which were associated with severity and co-occurred only in viruses from the 3c.2a1 clade. Additionally, we observed that intra-host diversity as a whole and on a specific set of gene segments increased with severity. These results support the use of whole genome sequencing as a tool for the identification of genetic traits associated with severe influenza in the context of influenza surveillance.

scholarly journals A Bacterial Analysis Platform: An Integrated System for Analysing Bacterial Whole Genome Sequencing Data for Clinical Diagnostics and Surveillance

PLoS ONE ◽  
2016 ◽  
Vol 11 (6) ◽  
pp. e0157718 ◽  
Author(s):  
Martin Christen Frølund Thomsen ◽  
Johanne Ahrenfeldt ◽  
Jose Luis Bellod Cisneros ◽  
Vanessa Jurtz ◽  
Mette Voldby Larsen ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Clinical Diagnostics ◽  
Integrated System ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
Analysis Platform

scholarly journals Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

2018 ◽  
Author(s):  
Lauge Farnaes ◽  
Amber Hildreth ◽  
Nathaly M. Sweeney ◽  
Michelle M. Clark ◽  
Shimul Chowdhury ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Clinical Utility ◽  
Genetic Disorders ◽  
Standard Of Care ◽  
Inpatient Cost ◽  
Whole Genome ◽  
Improved Outcomes ◽  
Historical Controls ◽  
Etiologic Diagnosis

ABSTRACTBACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.METHODSRetrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.FINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.DISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

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