scholarly journals Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

2019 ◽  
Author(s):  
Go Hun Seo ◽  
Taeho Kim ◽  
Jung-young Park ◽  
Jungsul Lee ◽  
Sehwan Kim ◽  
...  
Keyword(s):  
Family Member ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Whole Exome ◽  
Interpretation System ◽  
Automated Interpretation ◽  
Age Range

AbstractPurposeEVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders.MethodsDNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to WES. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments.ResultsThe average number of overlapping organ categories per patient was 4.5 ± 5.0. EVIDENCE reported a total 244 variants in 215 (65.1%) of the 330 probands. After clinical reassessment and/or family member testing, 196 variants were identified in 171 probands (51.8%), including 115 novel variants. These variants were confirmed as being responsible for 146 genetic disorders. One hundred-seven (54.6%) of the 196 variants were categorized as pathogenic or likely pathogenic before, and 146 (74.6%) after, clinical assessment and/or family member testing. Factors associated with a variant being confirmed as causative include rules, such as PVS1, PS1, PM1, PM5, and PP5, and similar symptom scores between that variant and a patient’s phenotype.ConclusionThis new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 51% improvement in diagnostic yield.

scholarly journals Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

2016 ◽  
Author(s):  
M Córdoba ◽  
SA Rodriguez-Quiroga ◽  
PA Vega ◽  
H Amartino ◽  
C Vázquez-Dusefante ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Low Income ◽  
Clinical Management ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Potential Cost ◽  
Low Income Country ◽  
Whole Exome ◽  
Neurogenetic Disorders

ABSTRACTClinical variability is a hallmark of neurogenetic disorders. They involve widespread neurological entities such as neuropathies, ataxias, myopathies, mitochondrial encephalopathies, leukodystrophies, epilepsy and intellectual disabilities. Despite the use of considerable time and resources, the diagnostic yield in this field has been disappointingly low. This etiologic search has been called a “diagnostic odyssey” for many families. Whole exome sequencing (WES) has proved to be useful across a variety of genetic disorders, simplifying the odyssey of many patients and their families and leading to subsequent changes in clinical management in a proportion of them. Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well, there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country. Herein, we report on a series of our first 40 consecutive cases that were selected for WES in a research-based neurogenetics laboratory. We demonstrated the clinical utility of WES in our patient cohort, obtaining a diagnostic yield of 40% (95% CI, 24.8%-55.2%), describing cases in which clinical management was altered, and suggesting the potential cost-effectiveness of WES as a single test by examining the number and types of tests that were performed prior to WES which added up to a median cost of $3537.6 ($2892 to $5084) for the diagnostic odysseys experienced by our cohort.

scholarly journals B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

2019 ◽  
Vol 46 (s1) ◽  
pp. S11
Author(s):  
L Gauquelin ◽  
T Hartley ◽  
M Tarnopolsky ◽  
DA Dyment ◽  
B Brais ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Cerebellar Atrophy ◽  
Clinical Findings ◽  
Disease Genes ◽  
Pathogenic Variants ◽  
Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

Genetic landscape of congenital disorders in patients from Southeast Asia: results from sequencing using a gene panel for Mendelian phenotypes

2020 ◽  
Vol 106 (1) ◽  
pp. 38-43 ◽  
Author(s):  
Heming Wei ◽  
Angeline Lai ◽  
Ee Shien Tan ◽  
Mark Jean Aan Koh ◽  
Ivy Ng ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Good Alternative ◽  
Gene Panel ◽  
Mendelian Disorders ◽  
Large Gene ◽  
Pathogenic Variants ◽  
Whole Exome

ObjectiveTo test the utility and diagnostic yield of a medical-exome gene panel for identifying pathogenic variants in Mendelian disorders.MethodsNext-generation sequencing was performed with the TruSight One gene panel (targeting 4813 genes) followed by MiSeq sequencing on 216 patients who presented with suspected genetic disorders as assessed by their attending physicians.ResultsThere were 56 pathogenic and 36 likely pathogenic variants across 57 genes identified in 87 patients. Causal mutations were more likely to be truncating and from patients with a prior clinical diagnosis. Another 18 promising variants need further evaluation for more evidence to meet the requirement for potential upgrade to pathogenic. Forty-five of the 92 clinically significant variants were novel.ConclusionThe 40.3% positive yield compares favourably with similar studies using either this panel or whole exome sequencing, demonstrating that large gene panels could be a good alternative to whole exome sequencing for quick genetic confirmation of Mendelian disorders.

scholarly journals SUN-721 Implementation of Whole Exome Sequencing for Clinical Diagnostics: A Prospective Busan Kyung-Sang Regional Co-Work Team Experience

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jeong Eun Lee ◽  
WooYeong Chung ◽  
BoLyun Lee ◽  
SooHyun Ku ◽  
Ga Won Jeon ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorder ◽  
Genetic Diseases ◽  
Clinical Diagnostics ◽  
Buccal Swab ◽  
Variant Interpretation ◽  
Pathogenic Variants ◽  
Whole Exome

Abstract Purpose: Next Generation Sequencing (NGS) technology is a highthroughput method for genome sequencing which assists clinicians with diagnosis of patients with suspected genetic disorders. This study was to investigate diagnostic yield and clinical utility of whole exome sequencing prospectively in the rare genetic diseases. Method: WES was performed a total of 178 patients with suspected genetic disorder. Buccal swab samples were collected from the patients to extract genomic DNA. WES and variant interpretation was conducted in 3 Billion Inc (Seoul, Republic of Korea), based on their own software. Patients’ phenotype was interpreted by clinical geneticists. Results: WES reported 117 variants (66.7%). According to the ACMG/AMP guidelines, there were 25 pathogenic variants (14%), 37 likely pathogenic variants (32%), and 55 VUS (31%). Among the 117 patients who detected variants, genotype-phenotype correlation was analyzed and resulted that 44 (38%) were found to be apparently causal mutation of the disease, 37 (32%) were not considered the cause of the disease, and 36 (31%) were withheld judgement. Of the VUS variants, 13% were likely to be the causal variants of the disease considering phenotype of patients. Conclusion: This study showed 38% of diagnostic yield in patients with unidentified genetic condition by using prospective WES based on automating variant interpretation system. In the diagnosis of rare genetic disease, we identified the need for a multi-disciplinary team to select appropriate subjects and interpret the clinical significance of the found genetic variants.

scholarly journals Whole Exome Sequencing Analysis in Fetal Skeletal Dysplasia Detected by Ultrasonography: An Analysis of 38 Cases

2021 ◽  
Vol 12 ◽  
Author(s):  
Ying Peng ◽  
Shuting Yang ◽  
Xiaoliang Huang ◽  
Jialun Pang ◽  
Jing Liu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Recurrence Risk ◽  
Snp Analysis ◽  
Sequencing Analysis ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Uncertain Significance

Background: Skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders that primarily affect bone and cartilage. This study aims to identify the genetic causes for fetal SDs, and evaluates the diagnostic yield of prenatal whole-exome sequencing (WES) for this disorder.Methods: WES was performed on 38 fetuses with sonographically identified SDs and normal results of karyotype and single nucleotide polymorphism (SNP) analysis. Candidate variants were selected by bioinformatics analysis, and verified by Sanger sequencing.Results: WES revealed pathogenic or likely pathogenic variants associated with SDs in 65.79% (25/38) of fetuses, variants of uncertain significance (VUS) in SDs-related genes in 10.53% (4/38) cases, and incidental findings in 31.58% (12/38) fetuses. The SDs-associated variants identified in the present study affected 10 genes, and 35.71% (10/28) of the variants were novel.Conclusion: WES has a high diagnostic rate for prenatal SDs, which improves pregnancy management, prenatal counseling and recurrence risk assessment for future pregnancies. The newly identified variants expanded mutation spectrum of this disorder.

scholarly journals A Bioinformatics Pipeline for Whole Exome Sequencing: Overview of the Processing and Steps from Raw Data to Downstream Analysis

2017 ◽  
Author(s):  
Narendra Meena ◽  
Praveen Mathur ◽  
Krishna Mohan Medicherla ◽  
Prashanth Suravajhala
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Rare Variants ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Variant Calling ◽  
Genome Project ◽  
Bioinformatics Pipeline ◽  
Whole Exome ◽  
Ngs Data

AbstractRecent advances in next generation sequencing (NGS) technologies have given an impetus to find causality for rare genetic disorders. Since 2005 and aftermath of the human genome project, efforts have been made to understand the rare variants of genetic disorders. Benchmarking the bioinformatics pipeline for whole exome sequencing (WES) has always been a challenge. In this protocol, we discuss detailed steps from quality check to analysis of the variants using a WES pipeline comparing them with reposited public NGS data and survey different techniques, algorithms and software tools used during each step. We observed that variant calling performed on exome and whole genome datasets have different metrics generated when compared to variant callers, GATK and VarScan with different parameters. Furthermore, we found that VarScan with strict parameters could recover 80-85% of high quality GATK SNPs with decreased sensitivity from NGS data. We believe our protocol in the form of pipeline can be used by researchers interested in performing WES analysis for genetic diseases and by large any clinical phenotypes.

scholarly journals One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver–Russell syndrome

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Robert Meyer ◽  
Matthias Begemann ◽  
Christian Thomas Hübner ◽  
Daniela Dey ◽  
Alma Kuechler ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Uniparental Disomy ◽  
Molecular Testing ◽  
Main Body ◽  
Comprehensive Overview ◽  
Maternal Uniparental Disomy ◽  
Whole Exome ◽  
Silver Russell Syndrome

Abstract Background Silver-Russell syndrome (SRS) is an imprinting disorder which is characterised by severe primordial growth retardation, relative macrocephaly and a typical facial gestalt. The clinical heterogeneity of SRS is reflected by a broad spectrum of molecular changes with hypomethylation in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat) as the most frequent findings. Monogenetic causes are rare, but a clinical overlap with numerous other disorders has been reported. However, a comprehensive overview on the contribution of mutations in differential diagnostic genes to phenotypes reminiscent to SRS is missing due to the lack of appropriate tests. With the implementation of next generation sequencing (NGS) tools this limitation can now be circumvented. Main body We analysed 75 patients referred for molecular testing for SRS by a NGS-based multigene panel, whole exome sequencing (WES), and trio-based WES. In 21/75 patients a disease-causing variant could be identified among them variants in known SRS genes (IGF2, PLAG1, HMGA2). Several patients carried variants in genes which have not yet been considered as differential diagnoses of SRS. Conclusions WES approaches significantly increase the diagnostic yield in patients referred for SRS testing. Several of the identified monogenetic disorders have a major impact on clinical management and genetic counseling.

scholarly journals Exome sequencing in paediatric patients with movement disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Anna Ka-Yee Kwong ◽  
Mandy Ho-Yin Tsang ◽  
Jasmine Lee-Fong Fung ◽  
Christopher Chun-Yu Mak ◽  
Kate Lok-San Chan ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Movement Disorders ◽  
Rare Variants ◽  
Diagnostic Yield ◽  
Neurological Diseases ◽  
Genetic Diagnosis ◽  
Potential Treatment ◽  
Paediatric Patients ◽  
Whole Exome

Abstract Background Movement disorders are a group of heterogeneous neurological diseases including hyperkinetic disorders with unwanted excess movements and hypokinetic disorders with reduction in the degree of movements. The objective of our study is to investigate the genetic etiology of a cohort of paediatric patients with movement disorders by whole exome sequencing and to review the potential treatment implications after a genetic diagnosis. Results We studied a cohort of 31 patients who have paediatric-onset movement disorders with unrevealing etiologies. Whole exome sequencing was performed and rare variants were interrogated for pathogenicity. Genetic diagnoses have been confirmed in 10 patients with disease-causing variants in CTNNB1, SPAST, ATP1A3, PURA, SLC2A1, KMT2B, ACTB, GNAO1 and SPG11. 80% (8/10) of patients with genetic diagnosis have potential treatment implications and treatments have been offered to them. One patient with KMT2B dystonia showed clinical improvement with decrease in dystonia after receiving globus pallidus interna deep brain stimulation. Conclusions A diagnostic yield of 32% (10/31) was reported in our cohort and this allows a better prediction of prognosis and contributes to a more effective clinical management. The study highlights the potential of implementing precision medicine in the patients.

scholarly journals A domestic cat whole exome sequencing resource for trait discovery

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alana R. Rodney ◽  
Reuben M. Buckley ◽  
Robert S. Fulton ◽  
Catrina Fronick ◽  
Todd Richmond ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diseases ◽  
Domestic Cat ◽  
Whole Genome Sequence ◽  
Exome Capture ◽  
Single Nucleotide Variants ◽  
Whole Exome ◽  
Olfactory Receptor Genes ◽  
Feline Model

AbstractOver 94 million domestic cats are susceptible to cancers and other common and rare diseases. Whole exome sequencing (WES) is a proven strategy to study these disease-causing variants. Presented is a 35.7 Mb exome capture design based on the annotated Felis_catus_9.0 genome assembly, covering 201,683 regions of the cat genome. Whole exome sequencing was conducted on 41 cats with known and unknown genetic diseases and traits, of which ten cats had matching whole genome sequence (WGS) data available, used to validate WES performance. At 80 × mean exome depth of coverage, 96.4% of on-target base coverage had a sequencing depth > 20-fold, while over 98% of single nucleotide variants (SNVs) identified by WGS were also identified by WES. Platform-specific SNVs were restricted to sex chromosomes and a small number of olfactory receptor genes. Within the 41 cats, we identified 31 previously known causal variants and discovered new gene candidate variants, including novel missense variance for polycystic kidney disease and atrichia in the Peterbald cat. These results show the utility of WES to identify novel gene candidate alleles for diseases and traits for the first time in a feline model.

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