ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
Development of an evidence-based algorithm that optimizes sensitivity and specificity in ES-based diagnostics of a clinically heterogeneous patient population.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Data from the ROPAD study corroborate an association between ITSN1 loss-of-function variants and Parkinson's disease.NPJ Parkinson's disease · 2026Article
- Pathogenic or Likely Pathogenic GRN Variants Are Found in 0.1% of Parkinson's Disease Patients.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Evaluation of false positive and false negative errors in targeted next generation sequencing.Genome biology · 2025Article
- Adult genomic medicine: lessons from a multisite study of 2700 patients.Genome medicine · 2025Article
- Bi-allelic variants in DAP3 result in reduced assembly of the mitoribosomal small subunit with altered apoptosis and a Perrault-syndrome-spectrum phenotype.American journal of human genetics · 2025Article
- Biallelic variants inmedRxiv : the preprint server for health sciences · 2024Article
- The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.American journal of human genetics · 2024Article
- Expanding the phenotype of PPP1R21-related neurodevelopmental disorder.Clinical genetics · 2024Article
- Potential of Artificial Intelligence to Accelerate Drug Development for Rare Diseases.Pharmaceutical medicine · 2024Article
- A homozygous MED11 C-terminal variant causes a lethal neurodegenerative disease.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition.American journal of medical genetics. Part A · 2022Article
- An integrated multiomic approach as an excellent tool for the diagnosis of metabolic diseases: our first 3720 patients.European journal of human genetics : EJHG · 2022Article
- Biallelic ADAM22 pathogenic variants cause progressive encephalopathy and infantile-onset refractory epilepsy.Brain : a journal of neurology · 2022Article
- Whole exome sequencing in a juvenile idiopathic arthritis large family with SERPINA1 gene mutations.BMC rheumatology · 2022Article
- El-Hattab-Alkuraya syndrome caused by biallelic WDR45B pathogenic variants: Further delineation of the phenotype and genotype.Clinical genetics · 2022Article
- PanelDesign: Integrating Epidemiological Information into the Design of Diagnostic NGS Gene Panels.Genes · 2022Article
- Article
- Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Biallelic variants inJournal of medical genetics · 2021Article
- LRRK2 Loss-of-Function Variants in Patients with Rare Diseases: No Evidence for a Phenotypic Impact.Movement disorders : official journal of the Movement Disorder Society · 2021Article
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeNext-generation sequencing (NGS) is rapidly replacing Sanger sequencing in genetic diagnostics. Sensitivity and specificity of NGS approaches are not well-defined, but can be estimated from applying NGS and Sanger sequencing in parallel. Utilizing this strategy, we aimed at optimizing exome sequencing (ES)-based diagnostics of a clinically diverse patient population.
methodsConsecutive DNA samples from unrelated patients with suspected genetic disease were exome-sequenced; comparatively nonstringent criteria were applied in variant calling. One thousand forty-eight variants in genes compatible with the clinical diagnosis were followed up by Sanger sequencing. Based on a set of variant-specific features, predictors for true positives and true negatives were developed.
resultsSanger sequencing confirmed 81.9% of ES-derived variants. Calls from the lower end of stringency accounted for the majority of the false positives, but also contained ~5% of the true positives. A predictor incorporating three variant-specific features classified 91.7% of variants with 100% specificity and 99.75% sensitivity. Confirmation status of the remaining variants (8.3%) was not predictable.
conclusionsCriteria for variant calling in ES-based diagnostics impact on specificity and sensitivity. Confirmatory sequencing for a proportion of variants, therefore, remains a necessity. Our study exemplifies how these variants can be defined on an empirical basis.
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