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

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.

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.

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 Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort

2020 ◽  
Vol 57 (8) ◽  
pp. 558-566 ◽  
Author(s):  
Xinran Dong ◽  
Bo Liu ◽  
Lin Yang ◽  
Huijun Wang ◽  
Bingbing Wu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Developmental Disorders ◽  
Chromosomal Microarray ◽  
Chromosomal Microarray Analysis ◽  
Sequencing Data ◽  
Single Nucleotide ◽  
Clinical Exome Sequencing ◽  
Clinical Scenarios ◽  
Combinational Analysis ◽  
Chinese Cohort

BackgroundDevelopmental disorders (DDs) are early onset disorders affecting 5%–10% of children worldwide. Chromosomal microarray analysis detecting CNVs is currently recommended as the first-tier test for DD diagnosis. However, this analysis omits a high percentage of disease-causing single nucleotide variations (SNVs) that warrant further sequencing. Currently, next-generation sequencing can be used in clinical scenarios detecting CNVs, and the use of exome sequencing in the DD cohort ahead of the microarray test has not been evaluated.MethodsClinical exome sequencing (CES) was performed on 1090 unrelated Chinese DD patients who were classified into five phenotype subgroups. CNVs and SNVs were both detected and analysed based on sequencing data.ResultsAn overall diagnostic rate of 41.38% was achieved with the combinational analysis of CNV and SNV. Over 12.02% of patients were diagnosed based on CNV, which was comparable with the published CMA diagnostic rate, while 0.74% were traditionally elusive cases who had dual diagnosis or apparently homozygous mutations that were clarified. The diagnostic rates among subgroups ranged from 21.82% to 50.32%. The top three recurrent cytobands with diagnostic CNVs were 15q11.2-q13.1, 22q11.21 and 7q11.23. The top three genes with diagnostic SNVs were: MECP2, SCN1A and SCN2A. Both the diagnostic rate and spectrums of CNVs and SNVs showed differences among the phenotype subgroups.ConclusionWith a higher diagnostic rate, more comprehensive observation of variations and lower cost compared with conventional strategies, simultaneous analysis of CNVs and SNVs based on CES showed potential as a new first-tier choice to diagnose DD.

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders

2015 ◽  
Vol 134 (9) ◽  
pp. 967-980 ◽  
Author(s):  
Tarunashree Yavarna ◽  
Nader Al-Dewik ◽  
Mariam Al-Mureikhi ◽  
Rehab Ali ◽  
Fatma Al-Mesaifri ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Diagnostic Yield ◽  
Middle Eastern ◽  
Mendelian Disorders ◽  
High Diagnostic Yield ◽  
Clinical Exome Sequencing
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