scholarly journals Novel BMD loci identified by whole genome sequencing and CRISPR editing in zebrafish: The NHLBI Trans-Omics for Precision Medicine (TOPMED) study

Bone Reports ◽  
2021 ◽  
Vol 14 ◽  
pp. 100765
Author(s):  
Yi-Hsiang Hsu ◽  
Joyce W. Tang ◽  
Hanfei Xu ◽  
Cecily Choy ◽  
May Montasser ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome

scholarly journals Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging

2020 ◽  
Vol 117 (6) ◽  
pp. 3053-3062 ◽  
Author(s):  
Ying-Chen Claire Hou ◽  
Hung-Chun Yu ◽  
Rick Martin ◽  
Elizabeth T. Cirulli ◽  
Natalie M. Schenker-Ahmed ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Clinical Laboratory ◽  
Descriptive Analysis ◽  
Disease Diagnosis ◽  
Whole Genome ◽  
Advanced Imaging ◽  
Family Medical History ◽  
Deep Phenotyping

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

scholarly journals Precision Medicine in Cats: Novel Niemann-Pick Type C1 Diagnosed by Whole-Genome Sequencing

2017 ◽  
Vol 31 (2) ◽  
pp. 539-544 ◽  
Author(s):  
D.A. Mauler ◽  
B. Gandolfi ◽  
C.R. Reinero ◽  
D.P. O'Brien ◽  
J.L. Spooner ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Niemann Pick

scholarly journals Assessing reproducibility of inherited variants detected with short-read whole genome sequencing

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Bohu Pan ◽  
Luyao Ren ◽  
Vitor Onuchic ◽  
Meijian Guan ◽  
Rebecca Kusko ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Short Read ◽  
Sequencing Platforms ◽  
The Impact ◽  
Two Populations

Abstract Background Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. Conclusions Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.

Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy

2018 ◽  
Vol 21 (12) ◽  
pp. 1086-1093 ◽  
Author(s):  
Eric S Ontiveros ◽  
Yu Ueda ◽  
Samantha P Harris ◽  
Joshua A Stern ◽  
Keyword(s):  
Heart Disease ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Allele Frequency ◽  
Genome Sequencing ◽  
Disease Status ◽  
Whole Genome ◽  
Proof Of Concept ◽  
Separate Cohort

Objectives The objective of this study was to perform a proof-of-concept experiment that validates a precision medicine approach to identify variants associated with hypertrophic cardiomyopathy (HCM). We hypothesized that whole-genome sequencing would identify variant(s) associated with HCM in two affected Maine Coon/Maine Coon cross cats when compared with 79 controls of various breeds. Methods Two affected and two control Maine Coon/Maine Coon cross cats had whole-genome sequencing performed at approximately × 30 coverage. Variants were called in these four cats and 77 cats of various breeds as part of the 99 Lives Cat Genome Sequencing Initiative ( http://felinegenetics.missouri.edu/99lives ) using Platypus v0.7.9.1, annotated with dbSNP ID, and variants’ effect predicted by SnpEff. Strict filtering criteria (alternate allele frequency >49%) were applied to identify homozygous-alternate or heterozygous variants in the two HCM-affected samples when compared with 79 controls of various breeds. Results A total of four variants were identified in the two Maine Coon/Maine Coon cross cats with HCM when compared with 79 controls after strict filtering. Three of the variants identified in genes MFSD12, BTN1A1 and SLITRK5 did not segregate with disease in a separate cohort of seven HCM-affected and five control Maine Coon/Maine Coon cross cats. The remaining variant MYBPC3 segregated with disease status. Furthermore, this gene was previously associated with heart disease and encodes for a protein with sarcomeric function. Conclusions and relevance This proof-of-concept experiment identified the previously reported MYBPC3 A31P Maine Coon variant in two HCM-affected cases. This result validates and highlights the power of whole-genome sequencing for feline precision medicine.

Feasibility of whole-genome sequencing in routine clinical practice.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3013-3013
Author(s):  
Kris Samsom ◽  
Kim Monkhorst ◽  
Luuk J. Schipper ◽  
Paul Roepman ◽  
Linda J.W. Bosch ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Error Rate ◽  
Routine Clinical Practice ◽  
Added Value ◽  
Comprehensive Cancer Center ◽  
Whole Genome ◽  
Tumor Material

3013 Background: In the next few years numerous drugs will be approved for defined genomic targets, most of these in a tumor agnostic manner. Identifying patients who can benefit from this is critical for the future success of precision medicine, ideally using a single comprehensive test to detect all possible biomarkers. The WIDE study (WGS Implementation in standard cancer Diagnostics for Every cancer patient) aimed to evaluate the feasibility, clinical validity (primary endpoints) and added value (secondary endpoint) of clinical grade Whole Genome Sequencing (cWGS) in routine clinical practice. Methods: cWGS was prospectively performed on 1,200 consecutive patients with (suspected) metastatic cancer. Tumor material was obtained during routine clinical procedures for both Standard-Of-Care (SOC) and cWGS. Next to securing a high quality specimen for SOC diagnostics, multiple frozen sections per patient were evaluated to identify the sample most suitable for WGS. cWGS was conducted independently of, but in parallel with SOC diagnostics, which included SOC molecular diagnostics (Moldx) for 48% of patients. cWGS and MolDx results were compared and discussed in a dedicated tumor board. Additional tests for resolving discordances were applied when needed. Results: cWGS was successfully performed in 69% (841/1217) of samples with a technical success rate of 97% (841/871). An insufficient amount of tumor cells ( < 20%) was the main reason for not completing cWGS (25%, 310/1217). cWGS turn-around-time (TAT), due to continuous improvements to the clinical procedure and cWGS pipeline over the course of the study, decreased to 10 working days. A total of 856 genomic biomarkers identified by SOC MolDx could be compared to cWGS results. Initial analyses of discordances revealed an error rate of 2.1% (18/856) for cWGS compared to a 1.0% (8/856) error rate for SOC Moldx. After optimizing cWGS and SOC pipelines based on these findings, error rates dropped to 0.6% (5/856) and 0.7% (6/856) for cWGS and SOC MolDx, respectively. Overall, cWGS identified clinically actionable (routine practice and experimental) biomarkers in 71% of all patients tested. Compared to SOC MolDx, cWGS identified one or more additional clinically actionable biomarkers in 54% (446/832) of patients. Interestingly, in patients who were not tested by SOC MolDx, actionable variants were identified by cWGS in 54% (153/282). Conclusions: The WIDE study has shown that cWGS is feasible in routine clinical practice in a comprehensive cancer center setting, using tumor material obtained during routine procedures. Furthermore, cWGS showed added value by identifying one or more additional clinically actionable biomarkers in 54% of patients including patients who had not received SOC Moldx. These outcomes have led to the successful adoption of cWGS at the Netherlands Cancer Institute as part of routine care, which will further facilitate precision medicine for cancer patients.

scholarly journals Abstract 4867: Exome- and whole genome sequencing for clinical evaluation and precision medicine in neuroblastoma

2017 ◽  
Author(s):  
Angela Martinez Monleon ◽  
Susanne Reinsbach ◽  
Niloufar Javanmardi ◽  
Anna Djos ◽  
Rose-Marie Sjoberg ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Clinical Evaluation ◽  
Whole Genome

scholarly journals Precision Medicine Advancements Using Whole Genome Sequencing, Noninvasive Whole Body Imaging, and Functional Diagnostics

2018 ◽  
Author(s):  
Ying-Chen Claire Hou ◽  
Hung-Chun Yu ◽  
Rick Martin ◽  
Natalie M. Schenker-Ahmed ◽  
Michael Hicks ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Coronary Artery Calcium ◽  
Whole Body ◽  
Whole Genome ◽  
Calcium Scoring ◽  
Coronary Artery Calcium Scoring ◽  
Precision Health

ABSTRACTWe report the results of a three-year precision medicine study that enrolled 1190 presumed healthy participants at a single research clinic. To enable a better assessment of disease risk and improve diagnosis, a precision health platform that integrates non-invasive functional measurements and clinical tests combined with whole genome sequencing (WGS) was developed. The platform included WGS, comprehensive quantitative non-contrast whole body (WB) and brain magnetic resonance imaging/angiography (MRI/MRA), computed tomography (CT) coronary artery calcium scoring, electrocardiogram, echocardiogram, continuous cardiac monitoring, clinical laboratory tests, and metabolomics. In our cohort, 24.3% had medically significant genetic findings (MSF) which may contribute to increased risk of disease. A total of 206 unique medically significant variants in 111 genes were identified, and forty individuals (3.4%) had more than one MSF. Phenotypic testing revealed: 34.2% of our cohort had a metabolomics profile suggestive of insulin resistance, 29.2% had elevated liver fat identified by MRI, 16.4% had clinically important cardiac structure or cardiac function abnormalities on cardiac MRI or ECHO, 8.8% had a high cardiovascular risk on CT coronary artery calcium scoring (Agatston calcium score > 400, Relative Risk of 7.2), 8.0% had arrhythmia found on continuous rhythm monitoring, 6.5% had cardiac conduction disorders found on EKG, 2% had previously undetected tumors detected by WB MRI, and 2.5% had previously undetected aneurysms detected by non-contrast MRI/MRA. Using family histories, personal histories, and test results, clinical and phenotypic findings were correlated with genomic findings in 130 study participants (63.1%) with high to moderate penetrance variants, suggesting the precision health platform improves the diagnostic process in asymptomatic individuals who were at risk. Cardiovascular and endocrine diseases achieved considerable clinical associations between MSFs and clinical phenotypes (89% and 72%, respectively). These findings demonstrate the value of integrating WGS and noninvasive clinical assessments for a rapid and integrated point-of-care clinical diagnosis of age-related diseases that contribute to premature mortality.

Sign in / Sign up

Export Citation Format

Share Document