ArticleBMC medical genomics2021
Characterizing sensitivity and coverage of clinical WGS as a diagnostic test for genetic disorders.
Article in BMC medical genomics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 44 citations in OpenAlex.
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- Metagenome-assembled genomes enhance bacterial read decontamination and variant calling in oral samples.iScience · 2025Article
- Advancements in Whole-Genome Sequencing Protocols: A Decade of In-House Operations and Quality Controls at the Tohoku Medical Megabank.JMA journal · 2025Review
- Clinical and data-driven optimization of Genomiser for rare disease patients: experience from the Hong Kong Genome Project.Briefings in bioinformatics · 2025Article
- Genetic Investigation of Inherited Variants in a Multiplex Autism Spectrum Disorder (ASD) Family Using Whole-Genome Sequencing (WGS).Iranian journal of public health · 2025Article
- Systematic genetic assessment of hearing loss using whole-genome sequencing identifies pathogenic variants.Experimental & molecular medicine · 2025Article
- Utility of genome sequencing in exome-negative pediatric patients with neurodevelopmental phenotypes.American journal of medical genetics. Part A · 2024Article
- Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome.Scientific reports · 2024Article
- Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma.Biomarker research · 2024Article
- Resolving unsolved whole-genome sequencing data in paediatric neurological disorders: a cohort study.Archives of disease in childhood · 2024Article
- Novel mutation leading to splice donor loss in a conserved site ofJournal of medical genetics · 2024Article
- Accelerated somatic mutation calling for whole-genome and whole-exome sequencing data from heterogenous tumor samples.Genome research · 2024Article
- Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases.Journal of medical genetics · 2024Article
- SMARTER-database: a tool to integrate SNP array datasets for sheep and goat breeds.GigaByte (Hong Kong, China) · 2024Article
- From haystack to high precision: advanced sequencing methods to unraveling circulating tumor DNA mutations.Frontiers in molecular biosciences · 2024Review
- The complete and fully-phased diploid genome of a male Han Chinese.Cell research · 2023Article
- The clinical utility and costs of whole-genome sequencing to detect cancer susceptibility variants-a multi-site prospective cohort study.Genome medicine · 2023Article
- Discrimination of monozygotic twins using mtDNA heteroplasmy through probe capture enrichment and massively parallel sequencing.International journal of legal medicine · 2023Article
- S-leaping: an efficient downsampling method for large high-throughput sequencing data.Bioinformatics (Oxford, England) · 2023Article
- The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies.Molecular genetics & genomic medicine · 2023Article
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Authors and funding
20 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundDue to its reduced cost and incomparable advantages, WGS is likely to lead to changes in clinical diagnosis of rare and undiagnosed diseases. However, the sensitivity and breadth of coverage of clinical WGS as a diagnostic test for genetic disorders has not been fully evaluated.
methodsHere, the performance of WGS in NA12878, the YH cell line, and the Chinese trios were measured by assessing their sensitivity, PPV, depth and breadth of coverage using MGISEQ-2000. We also compared the performance of WES and WGS using NA12878. The sensitivity and PPV were tested using the family-based trio design for the Chinese trios. We further developed a systematic WGS pipeline for the analysis of 8 clinical cases.
resultsIn general, the sensitivity and PPV for SNV/indel detection increased with mean depth and reached a plateau at an ~ 40X mean depth using down-sampling samples of NA12878. With a mean depth of 40X, the sensitivity of homozygous and heterozygous SNPs of NA12878 was > 99.25% and > 99.50%, respectively, and the PPV was 99.97% and 98.96%. Homozygous and heterozygous indels showed lower sensitivity and PPV. The sensitivity and PPV were still not 100% even with a mean depth of ~ 150X. We also observed a substantial variation in the sensitivity of CNV detection across different tools, especially in CNVs with a size less than 1 kb. In general, the breadth of coverage for disease-associated genes and CNVs increased with mean depth. The sensitivity and coverage of WGS (~ 40X) was better than WES (~ 120X). Among the Chinese trios with an ~ 40X mean depth, the sensitivity among offspring was > 99.48% and > 96.36% for SNP and indel detection, and the PPVs were 99.86% and 97.93%. All 12 previously validated variants in the 8 clinical cases were successfully detected using our WGS pipeline.
conclusionsThe current standard of a mean depth of 40X may be sufficient for SNV/indel detection and identification of most CNVs. It would be advisable for clinical scientists to determine the range of sensitivity and PPV for different classes of variants for a particular WGS pipeline, which would be useful when interpreting and delivering clinical reports.
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