Dataset Information

Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders.

ABSTRACT: Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND. The introduction of NGS allows for rapid and inexpensive large-scale genomic analysis and has led to enormous progress in deciphering monogenic forms of various genetic diseases. The simultaneous analysis of several potentially mutated genes improves the diagnostic process, making it faster and more efficient. The main aim of this report is to discuss the impact and advantages of the implementation of WES into the clinical diagnosis and management of ND. Therefore, we have performed a retrospective evaluation of WES application in 209 cases referred to the Department of Biochemistry and Molecular Genetics of the Hospital Clinic of Barcelona for WES sequencing derived from neurologists or clinical geneticists. In addition, we have further discussed some important facts regarding classification criteria for pathogenicity of rare variants, variants of unknown significance, deleterious variants, different clinical phenotypes, or frequency of actionable secondary findings. Different studies have shown that WES implementation establish diagnostic rate around 32% in ND and the continuous molecular diagnosis is essential to solve the remaining cases.

SUBMITTER: Alvarez-Mora MI

PROVIDER: S-EPMC10137364 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders.

Alvarez-Mora María Isabel MI Rodríguez-Revenga Laia L Jodar Meritxell M Potrony Miriam M Sanchez Aurora A Badenas Celia C Oriola Josep J Villanueva-Cañas José Luis JL Muñoz Esteban E Valldeoriola Francesc F Cámara Ana A Compta Yaroslau Y Carreño Mar M Martí María Jose MJ Sánchez-Valle Raquel R Madrigal Irene I

Genes 20230328 4

Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson's disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosin ...[more]

PMID: 37107571

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Project description:BackgroundGenomic assessment previously took months to result and was unable to impact clinical care in the pediatric intensive care unit (PICU). The advent of rapid exome sequencing potentially changes this. We investigated the impact of rapid exome sequencing in a pilot study on pediatric patients admitted to a single PICU with new-onset metabolic/neurologic disease.MethodsRapid exome sequencing (7 days to verbal result) was performed on (n = 10) PICU patients age < 6 years admitted with new-onset metabolic/neurologic disease. The primary outcome of interest was inpatient LOS, which served as a proxy for inpatient cost.ResultsA significant reduction in median LOS was identified when comparing PICU patients who underwent rapid exome sequencing to historical controls. From those patients who underwent rapid sequencing, five had likely pathogenic variants. In three cases with diagnostic genetic results, there was a modification to clinical care attributable to information provided by exome sequencing.ConclusionsThis pilot study demonstrates that rapid exome sequencing is feasible to do in the PICU, that genetic results can be returned quickly enough to impact critical care decision-making and management. In a select population of PICU patients, this technology may contribute to a decrease in hospital length of stay.ImpactTen prospectively enrolled PICU patients with defined clinical criteria and their parents underwent rapid exome sequencing. Fifty percent received a genetic diagnosis, and medical management was affected for 60% of those patients. Median hospital LOS was significantly decreased in this selective subset of PICU patients. Genetic disorders and congenital anomalies are a leading cause of pediatric mortality. Genomic assessment previously took weeks to months for results and was therefore unable to acutely impact clinical care in the pediatric intensive care unit (PICU). The recent advent of rapid exome sequencing changes this in selected patients. Rapid exome sequencing is feasible to do in a PICU. Genetic results can be returned quickly enough to impact critical care decision-making. When done in a carefully selected subset of pediatric patients, rapid exome sequencing can potentially decrease hospital LOS.

Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

Dataset Information

Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders.

Publications

Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders.

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