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Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory.

ABSTRACT: Sanger sequencing is currently considered the gold standard methodology for clinical molecular diagnostic testing. However, next-generation sequencing has already emerged as a much more efficient means to identify genetic variants within gene panels, the exome, or the genome. We sought to assess the accuracy of next-generation sequencing variant identification in our clinical genomics laboratory with the goal of establishing a quality score threshold for confirmatory Sanger-based testing.Confirmation data for reported results from 144 sequential clinical exome-sequencing cases (94 unique variants) and an additional set of 16 variants from comparable research samples were analyzed.Of the 110 total single-nucleotide variants analyzed, 103 variants had a quality score ?Q500, 103 (100%) of which were confirmed by Sanger sequencing. Of the remaining seven variants with quality scores

SUBMITTER: Strom SP

PROVIDER: S-EPMC4079763 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory.

Strom Samuel P SP Lee Hane H Das Kingshuk K Vilain Eric E Nelson Stanley F SF Grody Wayne W WW Deignan Joshua L JL

Genetics in medicine : official journal of the American College of Medical Genetics 20140109 7

<h4>Purpose</h4>Sanger sequencing is currently considered the gold standard methodology for clinical molecular diagnostic testing. However, next-generation sequencing has already emerged as a much more efficient means to identify genetic variants within gene panels, the exome, or the genome. We sought to assess the accuracy of next-generation sequencing variant identification in our clinical genomics laboratory with the goal of establishing a quality score threshold for confirmatory Sanger-based ...[more]

PMID: 24406459

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Project description:ImportanceCerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. 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.ObjectiveTo determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy.Design, setting, and participantsA 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.ExposuresExome sequencing with copy number variant detection.Main outcomes and measuresThe primary outcome was the molecular diagnostic yield of exome sequencing.ResultsAmong 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. 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. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care-based cohort. 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. 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).Conclusions and relevanceAmong 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. Further research is needed to understand the clinical implications of these findings.

Dataset Information

Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory.

Publications

Assessing the necessity of confirmatory testing for exome-sequencing results in a clinical molecular diagnostic laboratory.

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