Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study

2021 ◽  
Author(s):  
Jean-Philippe Mergnac ◽  
Arnaud Wiedemann ◽  
Céline Chery ◽  
Jean-Marie Ravel ◽  
Farès Namour ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Pediatric Patients ◽  
Genetic Test ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Referral Center ◽  
Clinical Exome Sequencing ◽  
Center Study

Diagnostic and Clinical Utility of Clinical Exome Sequencing in Children With Moderate and Severe Global Developmental Delay / Intellectual Disability

2019 ◽  
Vol 35 (2) ◽  
pp. 116-131 ◽  
Author(s):  
Jelena Ruml Stojanovic ◽  
Aleksandra Miletic ◽  
Borut Peterlin ◽  
Ales Maver ◽  
Marija Mijovic ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Developmental Delay ◽  
Clinical Utility ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Significant Proportion ◽  
Global Developmental Delay ◽  
Clinical Exome Sequencing ◽  
The Impact

Clinical exome sequencing is currently being used in diagnostics of various genetic disorders, but studies supporting its application in clinical setting are scarce. The aim of this study was to establish diagnostic and clinical utility of clinical exome sequencing in patients with moderate and severe global developmental delay/intellectual disability. Clinical diagnosis was made in 49 of 88 investigated patients, with overall diagnostic yield of 55.7%. Molecular findings are characterized in detail, including the impact of newly made diagnosis on clinical management. Several previously unreported genotype-phenotype correlations and 33 novel variants are described. Genetic and clinical data were shared through publicly available database. In conclusion, clinical exome sequencing allows identification of causative variants in a significant proportion of patients in investigated clinical subgroup. Compared to whole exome sequencing, it shows similar diagnostic and clinical utility with reduced costs, which could be of particular importance for institutions with limited resources.

scholarly journals Next-Generation Sequencing Gene Panels and “Solo” Clinical Exome Sequencing Applied in Structurally Abnormal Fetuses

2021 ◽  
pp. 1-11
Author(s):  
Montse Pauta ◽  
Berta Campos ◽  
Maria Segura-Puimedon ◽  
Gemma Arca ◽  
Alfons Nadal ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Monogenic Disease ◽  
Chromosomal Microarray Analysis ◽  
Next Generation ◽  
Clinical Exome Sequencing ◽  
Gene Panels ◽  
Generation Sequencing ◽  
Structural Anomalies

<b><i>Objective:</i></b> The aim of the study was to assess the diagnostic yield of 2 different next-generation sequencing (NGS) approaches: gene panel and “solo” clinical exome sequencing (solo-CES), in fetuses with structural anomalies and normal chromosomal microarray analysis (CMA), in the absence of a known familial mutation. <b><i>Methodology:</i></b> Gene panels encompassing from 2 to 140 genes, were applied mainly in persistent nuchal fold/fetal hydrops and in large hyperechogenic kidneys. Solo-CES, which entails sequencing the fetus alone and only interpreting the Online Mendelian Inheritance in Man genes, was performed in multisystem or recurrent structural anomalies. <b><i>Results:</i></b> During the study period (2015–2020), 153 NGS studies were performed in 148 structurally abnormal fetuses with a normal CMA. The overall diagnostic yield accounted for 35% (53/153) of samples and 36% (53/148) of the fetuses. Diagnostic yield with the gene panels was 31% (15/49), similar to 37% (38/104) in solo-CES. <b><i>Conclusions:</i></b> A monogenic disease was established as the underlying cause in 35% of selected fetal structural anomalies by gene panels and solo-CES.

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.

Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders

2020 ◽  
Vol 139 (11) ◽  
pp. 1381-1390
Author(s):  
Frederic Tran Mau-Them ◽  
Sebastien Moutton ◽  
Caroline Racine ◽  
Antonio Vitobello ◽  
Ange-Line Bruel ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Disorders ◽  
Diagnostic Yield ◽  
Efficient Strategy ◽  
Clinical Exome Sequencing ◽  
Second Tier ◽  
Molecular Bases

Improved diagnostic yield of neuromuscular disorders applying clinical exome sequencing in patients arising from a consanguineous population

2016 ◽  
Vol 91 (3) ◽  
pp. 386-402 ◽  
Author(s):  
Z. Fattahi ◽  
Z. Kalhor ◽  
M. Fadaee ◽  
R. Vazehan ◽  
E. Parsimehr ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Clinical Exome Sequencing

scholarly journals Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francisco Martinez-Granero ◽  
Fiona Blanco-Kelly ◽  
Carolina Sanchez-Jimeno ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Signs And Symptoms ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Comparative Genomic ◽  
Clinical Exome Sequencing

AbstractMost consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

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