scholarly journals Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease

Ophthalmology ◽  
2016 ◽  
Vol 123 (5) ◽  
pp. 1143-1150 ◽  
Author(s):  
Jamie M. Ellingford ◽  
Stephanie Barton ◽  
Sanjeev Bhaskar ◽  
Simon G. Williams ◽  
Panagiotis I. Sergouniotis ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Diagnostic Testing ◽  
Retinal Disease ◽  
Molecular Diagnostic ◽  
Whole Genome ◽  
Inherited Retinal Disease

scholarly journals Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

2017 ◽  
Vol 20 (4) ◽  
pp. 435-443 ◽  
Author(s):  
Anath C Lionel ◽  
Gregory Costain ◽  
Nasim Monfared ◽  
Susan Walker ◽  
Miriam S Reuter ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Gene Sequencing ◽  
Whole Genome ◽  
Targeted Gene Sequencing

scholarly journals Whole Genome Sequencing Resource of the European Larch Canker Pathogen Lachnellula willkommii for Molecular Diagnostic Marker Development

2020 ◽  
Vol 110 (7) ◽  
pp. 1255-1259
Author(s):  
Emily Giroux ◽  
Guillaume J. Bilodeau
Keyword(s):  
United States ◽  
North America ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Draft Genome ◽  
The United States ◽  
Molecular Diagnostic ◽  
Whole Genome ◽  
European Larch ◽  
The North

The filamentous ascomycete fungus Lachnellula willkommii is the causal agent of European larch canker (ELC), one of the most destructive diseases of larch in Europe and a regulated plant pathogen of quarantine significance in Canada and the United States. L. willkommii was first detected in Massachusetts, North America in 1927 on a larch plantation cultivated with nursery stock imported from Great Britain. Despite the decades of practices aimed at eliminating the pathogen, it has reappeared in coastal areas of Canada and the United States. There is concern ELC could spread throughout the range of eastern larch, a transcontinental species typical of the Boreal forest that spans the North American landscape. There is geographic range overlap between several nonpathogenic indigenous Lachnellula species and the reported distribution of L. willkommii in North America. Morphological and biological methods to distinguish L. willkommii are often inadequate as the fungus does not always produce the phenotypic structures that distinguish it from these other saprophytic Lachnellula species. Whole genome sequencing technologies were used to obtain the draft genome sequences of L. willkommii and six other Lachnellula species. Molecular markers identified from the genomic data may be used to discriminate L. willkommii from its nonpathogenic relatives.

Increased Diagnostic Yield of Spastic Paraplegia with or Without Cerebellar Ataxia Through Whole-Genome Sequencing

2019 ◽  
Vol 18 (4) ◽  
pp. 781-790 ◽  
Author(s):  
Aryun Kim ◽  
Kishore R. Kumar ◽  
Ryan L. Davis ◽  
Amali C. Mallawaarachchi ◽  
Velimir Gayevskiy ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Cerebellar Ataxia ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Whole Genome ◽  
Spastic Paraplegia

The Efficacy of Whole Genome Sequencing and RNA-Seq in the Diagnosis of Whole Exome Sequencing Negative Patients with Complex Neurological Phenotypes

2021 ◽  
Author(s):  
Bianca Blake ◽  
Lauren I. Brady ◽  
Nicholas A. Rouse ◽  
Peter Nagy ◽  
Mark A. Tarnopolsky
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Whole Genome ◽  
Rna Seq ◽  
Complete Coverage ◽  
Whole Exome ◽  
Chromosome Microarray

AbstractWhole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.

First tier rapid whole genome sequencing increases diagnostic yield and changes management in children admitted in intensive care

2021 ◽  
Vol 132 ◽  
pp. S102
Author(s):  
Guylaine D’Amours ◽  
Julie Gauthier ◽  
Fadi Hamdan ◽  
Audrey Meleu ◽  
Catalina Maftei ◽  
...  
Keyword(s):  
Intensive Care ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Whole Genome

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 of a sporadic primary immunodeficiency cohort

2018 ◽  
Author(s):  
James E. D. Thaventhiran ◽  
Hana Lango Allen ◽  
Oliver S. Burren ◽  
William Rae ◽  
Daniel Greene ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Primary Immunodeficiency ◽  
Genome Wide Association Study ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Common Variants ◽  
Phenotypic Complexity ◽  
A Genome

AbstractPrimary immunodeficiency (PID) is characterised by recurrent and often life-threatening infections, autoimmunity and cancer, and it presents major diagnostic and therapeutic challenges. Although the most severe forms present in early childhood, the majority of patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent, and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic PID genetic diagnosis is difficult and the role of genetics is not well defined. We addressed these challenges by performing whole genome sequencing (WGS) of a large PID cohort of 1,318 participants. Analysis of coding regions of 886 index cases found disease-causing mutations in known monogenic PID genes in 10.3%, while a Bayesian approach (BeviMed4) identified multiple potential new candidate genes, including IVNS1ABP. Exploration of the non-coding genome revealed deletions in regulatory regions which contribute to disease causation. Finally, a genome-wide association study (GWAS) identified PID-associated loci and uncovered evidence for co-localisation of, and interplay between, novel high penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to variable penetrance and phenotypic complexity in PID. Thus, a cohort-based WGS approach to PID diagnosis can increase diagnostic yield while deepening our understanding of the key pathways influencing human immune responsiveness.

Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies

Neurology ◽  
2021 ◽  
Vol 96 (13) ◽  
pp. e1770-e1782
Author(s):  
Elizabeth Emma Palmer ◽  
Rani Sachdev ◽  
Rebecca Macintosh ◽  
Uirá Souto Melo ◽  
Stefan Mundlos ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Chromosomal Microarray ◽  
Whole Genome ◽  
Structural Variants ◽  
Epileptic Encephalopathies ◽  
Complex Structural ◽  
Made In

ObjectiveTo assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE).MethodsWe performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15).ResultsEight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked.ConclusionWGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

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