ArticleGenetics in medicine : official journal of the American College of Medical Genetics2021
One in seven pathogenic variants can be challenging to detect by NGS: an analysis of 450,000 patients with implications for clinical sensitivity and genetic test implementation.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed.
- Genomic Strategies in Pediatric Care: Addressing Rare Diseases in Children.Children (Basel, Switzerland) · 2026Review
- Artificial Intelligence and Genomic Data Analysis: New Frontiers in Precision Medicine.International journal of molecular sciences · 2026Review
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- Blood-based RNA-Seq of 5412 individuals with rare disease identifies new candidate diagnoses in the National Genomic Research Library.medRxiv : the preprint server for health sciences · 2026Article
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- Long-Chain Fatty Acid Oxidation Disorder Genes: A Comprehensive Genetic Database of LC-FAOD Variants, Genotypes, and Phenotypes.Human mutation · 2026Article
- Healthcare professionals' perspectives on expanding newborn genomic screening in the emirate of Abu Dhabi, United Arab Emirates: insights from a cross-sectional study.Frontiers in public health · 2026Article
- Paired Exome-Based Comprehensive Genomic Profiling and Germline Genetic Testing for Unselected Patients With Colorectal Cancer in a Multicenter Prospective Study.Gastro hep advances · 2026Article
- Integrating Long-Read Nanopore Sequencing for Precision Resolution of Genomic Variants in Dystonia.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Compound Heterozygous Structural Variants in Cases with Unsolved PRKN-Associated Parkinson's Disease.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Targeted adaptive sampling enables clinical pharmacogenomics testing and genome-wide genotyping.Scientific reports · 2025Article
- Using artificial intelligence (AI) to model clinical variant reporting for next generation sequencing (NGS) oncology assays.BioData mining · 2025Article
- Gene Specific Pathogenicity Predictor for Chromatin-Remodeling BAF Complex-Associated Neurodevelopmental Disorders.bioRxiv : the preprint server for biology · 2025Article
- Identification of technically challenging variants: Whole-genome sequencing improves diagnostic yield in patients with high clinical suspicion of rare diseases.HGG advances · 2025Article
- S1- Leitlinie "Molekulargenetische Diagnostik mit Hochdurchsatz-Sequenzierverfahren (Massives Paralleles Sequenzieren, MPS)".Medizinische Genetik : Mitteilungsblatt des Berufsverbandes Medizinische Genetik e.V · 2025Article
- Unraveling the hidden complexity of cancer through long-read sequencing.Genome research · 2025Review
- Rapid Whole-Genome Sequencing in Critically Ill Infants and Children with Suspected, Undiagnosed Genetic Diseases: Evolution to a First-Tier Clinical Laboratory Test in the Era of Precision Medicine.Children (Basel, Switzerland) · 2025Review
- Returning genetic risk information for hereditary cancers to participants in a population-based cohort study in Japan.Journal of human genetics · 2025Article
- Application of Digital Polymerase Chain Reaction (dPCR) in Non-Invasive Prenatal Testing (NIPT).Biomolecules · 2025Review
Corrections and comments
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26 authors.
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Abstract
purposeTo evaluate the impact of technically challenging variants on the implementation, validation, and diagnostic yield of commonly used clinical genetic tests. Such variants include large indels, small copy-number variants (CNVs), complex alterations, and variants in low-complexity or segmentally duplicated regions.
methodsAn interlaboratory pilot study used synthetic specimens to assess detection of challenging variant types by various next-generation sequencing (NGS)-based workflows. One well-performing workflow was further validated and used in clinician-ordered testing of more than 450,000 patients.
resultsIn the interlaboratory study, only 2 of 13 challenging variants were detected by all 10 workflows, and just 3 workflows detected all 13. Limitations were also observed among 11 less-challenging indels. In clinical testing, 21.6% of patients carried one or more pathogenic variants, of which 13.8% (17,561) were classified as technically challenging. These variants were of diverse types, affecting 556 of 1,217 genes across hereditary cancer, cardiovascular, neurological, pediatric, reproductive carrier screening, and other indicated tests.
conclusionThe analytic and clinical sensitivity of NGS workflows can vary considerably, particularly for prevalent, technically challenging variants. This can have important implications for the design and validation of tests (by laboratories) and the selection of tests (by clinicians) for a wide range of clinical indications.
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