scholarly journals Post-mortem whole-exome sequencing (WES) with a focus on cardiac disease-associated genes in five young sudden unexplained death (SUD) cases

2016 ◽  
Vol 130 (4) ◽  
pp. 1011-1021 ◽  
Author(s):  
Jacqueline Neubauer ◽  
Cordula Haas ◽  
Christine Bartsch ◽  
Argelia Medeiros-Domingo ◽  
Wolfgang Berger
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Cardiac Disease ◽  
Post Mortem ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome ◽  
Disease Associated Genes

scholarly journals Post-mortem Whole Exome Sequencing with Gene-Specific Analysis for Autopsy-Negative Sudden Unexplained Death in the Young: A Case Series

2014 ◽  
Vol 36 (4) ◽  
pp. 768-778 ◽  
Author(s):  
Nupoor Narula ◽  
David J. Tester ◽  
Anna Paulmichl ◽  
Joseph J. Maleszewski ◽  
Michael J. Ackerman
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Case Series ◽  
Post Mortem ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome ◽  
Specific Analysis

scholarly journals Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Elias L. Salfati ◽  
Emily G. Spencer ◽  
Sarah E. Topol ◽  
Evan D. Muse ◽  
Manuel Rueda ◽  
...  
Keyword(s):  
Sudden Death ◽  
Rare Disease ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Molecular Diagnostic ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

Abstract 15841: Whole Exome Sequencing and Analysis for Sudden Unexplained Death in the Young: A Case Series

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Nupoor Narula ◽  
David J Tester ◽  
Anna Paulmichl ◽  
Joseph J Maleszewski ◽  
Michael J Ackerman
Keyword(s):  
Sudden Death ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Effective Means ◽  
Susceptibility Gene ◽  
Case Series ◽  
Susceptibility Genes ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Whole Exome

Introduction: Annually, thousands of sudden deaths in individuals under the age of 35 years remain unexplained following a medico-legal autopsy and are termed autopsy negative sudden unexplained death in the young (SUDY). Cardiomyopathies, channelopathies, and metabolic disorders may underlie a significant number of SUDY cases. Previously, we demonstrated that 25% of autopsy-negative SUDY cases had mutations in the 4 major cardiac ion channel genes ( KCNQ1, KCNH2, SCN5A , and RYR2 ). However, over 100 sudden death-susceptibility genes have been discovered and may be implicated in SUDY. Objective: We explored the utility of whole exome sequencing (WES) followed by gene-specific surveillance as an efficient and effective means of performing post-mortem genetic testing in SUDY. Methods: Postmortem WES was performed on 14 consecutively-referred white SUDY victims (57% men; average age at death 17.4 ± 8.6 years) using the Agilent SureSelect Human All Exon V4+UTR capture kit and an Illumina HiSeq 2000 sequencer. Following variant alignment (hg19) and annotation, 117 cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes were surveyed to identify putative SUDY-associated mutations. Potentially pathogenic variants had to be non-synonymous and ultra-rare [i.e. absent in all 3 evaluated exome databases (1,000 Genome Project, the NHLBI GO Exome Sequencing Project, and Exome Chip Design)]. Results: On average, each SUDY case had 12,758 ± 2016 non-synonymous variants, of which 79 ± 15 localized to the 117 evaluated genes. Overall, 8 unique, ultra-rare variants (7 missense, 1 in-frame insertion) identified in 6 genes (3 in TTN ; 1 each in CACNA1C, JPH2, MYH7, VCL, RYR2 ) were detected in 7 of 14 cases (50%). Of the 7 missense alterations, 2 (T171M- CACNA1C , I22160T- TTN ) were predicted damaging by 3 in-silico tools. Conclusions: Although WES and gene-specific surveillance is an efficient and effective strategy to detect rare, potentially lethal, genetic variants, the accurate interpretation of each variant is daunting. Importantly, rarity, even ultra-rarity, does not equal pathogenicity even when the ultra-rare variant resides within a so-called sudden death-susceptibility gene.

scholarly journals Unveiling a sudden unexplained death case by whole exome sequencing and bioinformatic analysis

2020 ◽  
Vol 8 (4) ◽  
Author(s):  
Martina Modena ◽  
Vincenzo Castiglione ◽  
Paolo Aretini ◽  
Chiara M. Mazzanti ◽  
Enrica Chiti ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Bioinformatic Analysis ◽  
Sudden Unexplained Death ◽  
Unexplained Death ◽  
Death Case ◽  
Whole Exome

scholarly journals WEScover: selection between clinical whole exome sequencing and gene panel testing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
In-Hee Lee ◽  
Yufei Lin ◽  
William Jefferson Alvarez ◽  
Carles Hernandez-Ferrer ◽  
Kenneth D. Mandl ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Web Application ◽  
Gene Panel ◽  
False Negatives ◽  
Panel Testing ◽  
Whole Exome ◽  
Gene Panel Testing ◽  
Disease Associated Genes ◽  
Targeted Gene Panel Testing

Abstract Background Whole exome sequencing (WES) is widely adopted in clinical and research settings; however, one of the practical concerns is the potential false negatives due to incomplete breadth and depth of coverage for several exons in clinically implicated genes. In some cases, a targeted gene panel testing may be a dependable option to ascertain true negatives for genomic variants in known disease-associated genes. We developed a web-based tool to quickly gauge whether all genes of interest would be reliably covered by WES or whether targeted gene panel testing should be considered instead to minimize false negatives in candidate genes. Results WEScover is a novel web application that provides an intuitive user interface for discovering breadth and depth of coverage across population-scale WES datasets, searching either by phenotype, by targeted gene panel(s) or by gene(s). Moreover, the application shows metrics from the Genome Aggregation Database to provide gene-centric view on breadth of coverage. Conclusions WEScover allows users to efficiently query genes and phenotypes for the coverage of associated exons by WES and recommends use of panel tests for the genes with potential incomplete coverage by WES.

scholarly journals Quality threshold evaluation of Sanger confirmation for results of whole exome sequencing in clinically diagnostic setting

2020 ◽  
Author(s):  
Go Hun Seo ◽  
Hyeri Kim ◽  
Minjeong Kye ◽  
Jung-Young Park ◽  
Dong-gun Won ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Turnaround Time ◽  
Quality Score ◽  
Single Nucleotide Variants ◽  
Whole Exome ◽  
Disease Associated Genes ◽  
Quality Threshold ◽  
Allele Fraction

AbstractBackgroundWith the ability to simultaneously sequence more than 5,000 disease-associated genes, next-generation sequencing (NGS) has replaced Sanger sequencing as the preferred method in the diagnostic field at the laboratory level. However, Sanger sequencing has been used routinely to confirm identified variants prior to reporting results. This validation process causes a turnaround time delay and cost increase. Thus, this study aimed to set a quality threshold that does not require Sanger confirmation by analyzing the characteristics of identified variants from whole exome sequencing (WES).MethodsOur study analyzed data on a total of 694 disease-causing variants from 578 WES samples that had been diagnosed with suspected genetic disease. These samples were sequenced by Novaseq6000 and Exome Research Panel v2. All 694 variants (513 single-nucleotide variants (SNVs) and 181 indels) were validated by Sanger sequencing.ResultsA total of 693 variants included 512 SNVs and 181 indels from 578 patients and 367 genes. Five hundred seven heterozygous SNVs with at > 250 quality score and > 0.3 allele fraction were 100% confirmed by Sanger sequencing. Five heterozygous variants and one homozygous variant were not confirmed by Sanger sequencing, which showed 98.8% accuracy. There were 146 heterozygous variants and 35 homozygous variants among 181 indels, of which 11 heterozygous variants were not confirmed by Sanger sequencing (93.9% accuracy). Five non-confirmed variants with high quality were not identified on the ram .bam file.ConclusionOur results indicate that Sanger confirmation is not necessary for exome-derived SNVs with > 250 quality score and 0.3 > allele fraction set to an appropriate quality threshold. Indels or SNVs that do not meet the quality threshold should be reviewed by raw .bam file and Sanger confirmation should be performed to ensure accurate reporting.

scholarly journals Whole exome sequencing reveals putatively novel associations in retinopathies and drusen formation

2021 ◽  
Author(s):  
Lance P. Doucette ◽  
Nicole C. L. Noel ◽  
Yi Zhai ◽  
Manlong Xu ◽  
Oana Caluseriu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Research Setting ◽  
Genetic Etiology ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Clinical Investigations ◽  
Whole Exome ◽  
Disease Associated Genes ◽  
Novel Associations

AbstractInherited retinal dystrophies (IRDs) affect 1 in 3000 individuals worldwide and are genetically heterogeneous, with over 270 identified genes and loci; however, there are still many identified disorders with no current genetic etiology. Whole exome sequencing (WES) provides a hypothesis-free first examination of IRD patients in either a clinical or research setting to identify the genetic cause of disease. We present a study of IRD in ten families from Alberta, Canada, through the lens of novel gene discovery. We identify the genetic etiology of IRDs in three of the families to be variants in known disease-associated genes, previously missed by clinical investigations. In addition, we identify two potentially novel associations: LRP1 in early-onset drusen formation and UBE2U in a multi-system condition presenting with retinoschisis, cataracts, learning disabilities, and developmental delay. We also describe interesting results in our unsolved cases to provide further information to other investigators of these blinding conditions.

Whole Exome Sequencing (WES) in Familien mit linksventrikulärer Ausfluβtraktobstruktion (LVOTO)

2014 ◽  
Vol 62 (S 02) ◽  
Author(s):  
M. Hitz ◽  
S. Al-Turki ◽  
A. Schalinski ◽  
U. Bauer ◽  
T. Pickardt ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Whole Exome
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