Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome).  |  Findings  Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS) J Med Genet. Prof. Rose-Mary Boustany. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. High-throughput sequencing (HTS) has become a widespread diagnostic tool in various genetic conditions, including epilepsy (1), vastly improving molecular diagnosis. As whole exome sequencing (WES) becomes more widely used in the clinical realm, a wealth of unanalyzed information will be routinely generated. By using exome sequencing, we obtained a diagnostic yield of 34.4%. When applied to all 672 patients from the exome sequencing study, ExomeDepth identified eleven diagnostically relevant CNVs ranging in size from a two exon deletion to whole chromosome duplications, as well as numerous other CNVs with varying clinical significance. Cost-effectiveness analysis of using the TBX6-associated congenital scoliosis risk score (TACScore) in genetic diagnosis of congenital scoliosis. In this cross-sectional study that included 2 independent cohorts of 1526 patients with cerebral palsy, the molecular diagnostic yield of exome sequencing was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Using WES read depth data to predict copy number variation (CNV) could extend the diagnostic utility of this previously underutilized data by providing clinically important information such as previously unsuspected deletions or duplications. As whole exome sequencing (WES) becomes more widely used in the clinical realm, a wealth of unanalyzed information will be routinely generated. What is the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) among patients with cerebral palsy? Among 181 patients in the health care–based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. Exome sequencing has transformed genetic diagnosis after birth, but its usefulness for prenatal diagnosis is still emerging. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. Conclusions and Relevance  In a sample of patients with undiagnosed, suspected genetic conditions, a certain type of exome sequencing method was associated with a higher molecular diagnostic yield … The diagnostic yield of CES, commonly estimated at ~25%, is high compared to other diagnostic tools, including molecular karyotyping, which is officially endorsed by professional societies as a first-tier test 2.3. doi: 10.1002/mgg3.1453. Further research is needed to understand the clinical implications of these findings. Privacy Policy| A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Its clinical utility has been proven in epileptic encephalopathies and in mixed epilepsy cohorts (2–11); and in neurodevelopmental disorders (12–14) i… 2020 Oct;8(10):e1453.  |  See rights and permissions. Exome Sequencing in Fetuses Enrolled by US Anomalies (Regardless of the Affected Organ) Diagnostic yield of these papers ranges from 9% to 47%, with an average of 28%, and a higher rate for fetuses showing multiple malformations. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. Meaning  Challenges in Clinical Electrocardiography, Clinical Implications of Basic Neuroscience, Health Care Economics, Insurance, Payment, Scientific Discovery and the Future of Medicine, United States Preventive Services Task Force. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). Professor of Pediatrics and Adolescent Medicine, Beirut (NEJM, 2020) examined the diagnostic yield of exome sequencing for single-gene disorders in unexplained NIHF METHODS: Case-series Participants Consecutive unexplained cases of NIHF Definition of NIHF: Following findings alone or in combination … JAMA. National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients). Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening. 2020; 98:562–570. The identification of a molecular diagnosis for certain genetic disorders from this study could inform … To improve this, University of Groningen researchers use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1–51 years). The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Our diagnostic rate is within the range of 21–32%, seen in several studies of diagnostic yield for exome sequencing performed on fetal samples (Drury et al., 2015; Fu et al., 2018; Normand et al., 2018; Daum et al., 2019), and close to a diagnostic rate of 36.7% from exome sequencing of 278 infants in an intensive care unit (Meng et al., 2017). In the subset of 37 individuals with CDH+/CHD, a definitive (n=9; 24%) or probable (n=3; 8%) diagnosis was made in 12 individuals for a diagnostic yield of 32% (12/37). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted. Nonimmune hydrops … Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Seo GH, Kim T, Choi IH, et al. … HHS Background Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). Clipboard, Search History, and several other advanced features are temporarily unavailable. Moreno-De-Luca A, Millan F, Pesacreta DR, et al. • The rate of diagnoses was higher in complex dystonia. The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Diagnostic Yield of Exome Sequencing in the Patients. To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. 4 The primary aim of this study was to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. 37 Moreover, as shown in 30 cases, putatively pathogenic variants were … This opportunistic analysis of WES data yields an additional 1.6% of patients in this study with pathogenic or likely … Bhatia et al 2 further showed that using whole exome and whole genome sequencing (WGS) led to a diagnostic yield of 38% and 33%, respectively, in their Asian cohort. This site needs JavaScript to work properly. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (by comparative genomic hybridisation microarray and/or single-nucleotide polymorphism arrays), clinical exome sequencing and whole-genome sequencing offered in the Baylor Genetics Laboratory (http://bmgl.com). Senior Director, Genomics and Content, Personalis, Inc, Biography. Methods DNA from 330 probands (age range, 0–68 years) with suspected genetic disorders were subjected to WES. They show that this … 4.1.1. The diagnostic yield in our study is in line with other studies describing targeted or exome-wide analyses for heterogeneous groups of PID patients [5, 11, 54, 55]. All Rights Reserved. Would you like email updates of new search results? Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. It consists of two steps: the first step is to select only the subset of DNA that encodes proteins. Selected studies included those with more than three cases, with initiation of testing based upon prenatal phenotype only and that included cases in which CMA or karyotyping was negative. doi:10.1001/jama.2020.26148. What is the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) among patients with cerebral palsy? Increased Diagnostic Yield and Associated Patterns. Epub 2020 Aug 20. 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Clinical exome sequencing (CES) is currently a routine pediatric diagnostic tool that has demonstrated an average diagnostic yield of 25% for patients with a wide range of indications , , .The incidence of genetic disorders in the Arab countries, including the UAE, is extremely high and placing a burden of an estimated total annual cost of not less than $13 billion to the economy. In a sample of patients with undiagnosed, suspected genetic conditions, a certain type of exome sequencing method was associated with a higher molecular diagnostic yield … All Rights Reserved, 2021;325(5):467-475. doi:10.1001/jama.2020.26148. clinical genetics; diagnostics; genetics; molecular genetics. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. a) The histogram of diagnostic rates in different ID cohorts. Diagnostic yield in ID cohort (n = 95) by subgroup distribution through whole genome low-coverage sequencing and medical exome sequencing. Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. 2020 Sep 15;15(1):250. doi: 10.1186/s13023-020-01537-y. The relatively high yield can be influenced by familial cases and consanguinity [33,35,36]. Customize your JAMA Network experience by selecting one or more topics from the list below. Objective  ES enabled the molecular diagnosis/classification of patients with EOS. Exome sequencing should not be pursued as a means to an end, as attempting to reduce diagnostic uncertainty often only reveals the reality of a greater “genomic uncertainty” (9, 10). Methods: Yang Y, Zhao S, Zhang Y, Wang S, Shao J, Liu B, Li Y, Yan Z, Niu Y, Li X, Wang L, Ye Y, Weng X, Wu Z; Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study, Zhang J, Wu N. Mol Genet Genomic Med. to download free article PDFs, To compare the diagnostic yields of exome sequencing versus targeted gene panels in phenocopy cases, we retrospectively chose a commercial panel of a size < 25 kb (billable panel size in the German statutory health insurance system) covering the genes associated with the tentative clinical diagnosis (between 6 and 10 genes) and 1 comprehensive hereditary kidney disease panel (272 genes). A successful diagnosis requires that the disease gene is known, the gene is included in the exome capture and that the mutation type is detectable by the sequencing technology. Exposures  Despite the apparent incremental yield of prenatal exome sequencing in congenital heart disease, the routine application of such a policy would require the adoption of robust bioinformatic, clinical and ethical pathways. Furthermore, the literature is enriched with 52 convincing candidate genes … Question  To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Diagnostic Exome Sequencing: Diagnostic Yield, Novel Gene Discovery, Expected and Unexpected Results BACKGROUND Over the last three years, the application of whole exome sequencing in a clinical diagnostic setting (DES) has transformed the diagnosis and … The incremental … Design, Setting, and Participants  1. A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care–based cohort with data accrued between 2007 and 2017. Purpose EVIDENCE, an automated interpretation system, has been developed to facilitate the entire process of whole exome sequencing (WES) analyses. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Abstract. Accessibility Statement, Early, Accurate Diagnosis and Early Intervention in Cerebral Palsy, Iona Novak, PhD; Cathy Morgan, PhD; Lars Adde, PhD; James Blackman, PhD; Roslyn N. Boyd, PhD; Janice Brunstrom-Hernandez, MD; Giovanni Cioni, MD; Diane Damiano, PhD; Johanna Darrah, PhD; Ann-Christin Eliasson, PhD; Linda S. de Vries, PhD; Christa Einspieler, PhD; Michael Fahey, PhD; Darcy Fehlings, PhD; Donna M. Ferriero, MD; Linda Fetters, PhD; Simona Fiori, PhD; Hans Forssberg, PhD; Andrew M. Gordon, PhD; Susan Greaves, PhD; Andrea Guzzetta, PhD; Mijna Hadders-Algra, PhD; Regina Harbourne, PhD; Angelina Kakooza-Mwesige, PhD; Petra Karlsson, PhD; Lena Krumlinde-Sundholm, PhD; Beatrice Latal, MD; Alison Loughran-Fowlds, PhD; Nathalie Maitre, PhD; Sarah McIntyre, PhD; Garey Noritz, MD; Lindsay Pennington, PhD; Domenico M. Romeo, PhD; Roberta Shepherd, PhD; Alicia J. Spittle, PhD; Marelle Thornton, DipEd; Jane Valentine, MRCP; Karen Walker, PhD; Robert White, MBA; Nadia Badawi, PhD. A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care–based cohort with data accrued between 2007 and 2017. USA.gov. MEDLINE, EMBASE, CINAHL and ClinicalTrials.gov (January 2000 to October 2019) databases were searched electronically for studies reporting on the diagnostic yield of ES in prenatally diagnosed CHD. P01 HD084387/HD/NICHD NIH HHS/United States, U54 HG006542/HG/NHGRI NIH HHS/United States, UM1 HG006542/HG/NHGRI NIH HHS/United States, R35 NS105078/NS/NINDS NIH HHS/United States, K08 HG008986/HG/NHGRI NIH HHS/United States. Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Results The overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. Exome sequencing with copy number variant detection. In addition, three provisional diagnoses were made. Individuals with CDH+ for whom a definitive, probable or provisional diagnosis was made by exome sequencing. Familial testing can increase diagnostic yield relative to proband-only exome sequencing. No commercial re-use. © 2021 American Medical Association. The diagnostic yield of exome and genome sequencing remains low (8–70%), due to incomplete knowledge on the genes that cause disease. Conclusion: This study identified pathogenic and likely pathogenic variants among some patients with cerebral palsy, although further research is needed to understand the clinical implications of these findings. RNA sequencing has been used as a secondary tool to help prioritize disease gene candidates identified with exome and genome sequencing, and it has been shown to increase diagnostic yield … This study investigated the diagnostic yield of EVIDENCE in patients suspected genetic disorders. When applied to all 672 patients from the exome sequencing study, ExomeDepth identified eleven diagnostically relevant CNVs ranging in size from a two exon deletion to whole chromosome duplications, as well as numerous other CNVs with varying clinical significance. The results show an apparent incremental yield of exome sequencing in these cases. 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Continue, '' you are agreeing to our, 2021 American Medical.... Operative EOS pairs are able to indicate the likelihood of gaining a molecular diagnosis certain...