ABSTRACT
Purpose
Next-generation sequencing (NGS) has revolutionized the diagnostic process for rare/ultrarare
conditions. However, diagnosis rates differ between analytical pipelines. In the National
Institutes of Health-Undiagnosed Diseases Network (UDN) study, each individual’s NGS
data are concurrently analyzed by the UDN sequencing core laboratory and the clinical
sites. We examined the outcomes of this practice.
Methods
A retrospective review was performed at 2 UDN clinical sites to compare the variants
and diagnoses/candidate genes identified with the dual analyses of the NGS data.
Results
In total, 95 individuals had 100 diagnoses/candidate genes. There was 59% concordance
between the UDN sequencing core laboratories and the clinical sites in identifying
diagnoses/candidate genes. The core laboratory provided more diagnoses, whereas the
clinical sites prioritized more research variants/candidate genes (P < .001). The clinical sites solely identified 15% of the diagnoses/candidate genes.
The differences between the 2 pipelines were more often because of variant prioritization
disparities than variant detection.
Conclusion
The unique dual analysis of NGS data in the UDN synergistically enhances outcomes.
The core laboratory provided a clinical analysis with more diagnoses and the clinical
sites prioritized more research variants/candidate genes. Implementing such concurrent
dual analyses in other genomic research studies and clinical settings can improve
both variant detection and prioritization.
Keywords
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References
- The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities.Am J Hum Genet. 2015; 97: 199-215https://doi.org/10.1016/j.ajhg.2015.06.009
- Effect of genetic diagnosis on patients with previously undiagnosed disease.NEngl J Med. 2018; 379: 2131-2139https://doi.org/10.1056/NEJMoa1714458
- Clinical application of exome sequencing in undiagnosed genetic conditions.J Med Genet. 2012; 49: 353-361https://doi.org/10.1136/jmedgenet-2012-100819
- Clinical whole-exome sequencing for the diagnosis of Mendelian disorders.N Engl J Med. 2013; 369: 1502-1511https://doi.org/10.1056/NEJMoa1306555
- Molecular findings among patients referred for clinical whole-exome sequencing.JAMA. 2014; 312: 1870-1879https://doi.org/10.1001/jama.2014.14601
- Clinical exome sequencing for genetic identification of rare Mendelian disorders.JAMA. 2014; 312: 1880-1887https://doi.org/10.1001/jama.2014.14604
- Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care.Clin Genet. 2016; 89: 275-284https://doi.org/10.1111/cge.12654
- The clinical utility of exome and genome sequencing across clinical indications: a systematic review.Hum Genet. 2021; 140: 1403-1416https://doi.org/10.1007/s00439-021-02331-x
- Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.Genet Med. 2018; 20: 435-443https://doi.org/10.1038/gim.2017.119
- Rapid whole genome sequencing has clinical utility in children in the PICU.Pediatr Crit Care Med. 2019; 20: 1007-1020https://doi.org/10.1097/PCC.0000000000002056
- Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings.Lancet Respir Med. 2015; 3: 377-387https://doi.org/10.1016/S2213-2600(15)00139-3
- Genome sequencing identifies major causes of severe intellectual disability.Nature. 2014; 511: 344-347https://doi.org/10.1038/nature13394
- Reanalysis of clinical exome sequencing Data.N Engl J Med. 2019; 380: 2478-2480https://doi.org/10.1056/NEJMc1812033
- Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children.Intensive Care Med. 2019; 45: 627-636https://doi.org/10.1007/s00134-019-05552-x
- A comprehensive iterative approach is highly effective in diagnosing individuals who are exome negative.Genet Med. 2019; 21: 161-172https://doi.org/10.1038/s41436-018-0044-2
- Lessons learned from additional research analyses of unsolved clinical exome cases.Genome Med. 2017; 9: 26https://doi.org/10.1186/s13073-017-0412-6
- The importance of dynamic re-analysis in diagnostic whole exome sequencing.J Med Genet. 2017; 54: 155-156https://doi.org/10.1136/jmedgenet-2016-104306
- Reanalysis of exome negative patients with rare disease: a pragmatic workflow for diagnostic applications.Genome Med. 2022; 14: 66https://doi.org/10.1186/s13073-022-01069-z
- Systematic reanalysis of clinical exome data yields additional diagnoses: implications for providers.Genet Med. 2017; 19: 209-214https://doi.org/10.1038/gim.2016.88
- Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.Genet Med. 2018; 20: 1564-1574https://doi.org/10.1038/gim.2018.39
- Systematic reanalysis of genomic data improves quality of variant interpretation.Clin Genet. 2018; 94: 174-178https://doi.org/10.1111/cge.13259
- Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases.Genome Med. 2019; 11: 83https://doi.org/10.1186/s13073-019-0702-2
- The Epilepsy Genetics Initiative: systematic reanalysis of diagnostic exomes increases yield.Epilepsia. 2019; 60: 797-806https://doi.org/10.1111/epi.14698
- Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science.Genet Med. 2021; 23: 259-271https://doi.org/10.1038/s41436-020-00984-z
- Low concordance of multiple variant-calling pipelines: practical implications for exome and genome sequencing.Genome Med. 2013; 5: 28https://doi.org/10.1186/gm432
- Standards and guidelines for validating next-generation sequencing bioinformatics pipelines: a joint recommendation of the Association for Molecular Pathology and the College of American Pathologists.J Mol Diagn. 2018; 20: 4-27https://doi.org/10.1016/j.jmoldx.2017.11.003
- Limitations of the human reference genome for personalized genomics.PLoS One. 2012; 7e40294https://doi.org/10.1371/journal.pone.0040294
- An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge.Genome Biol. 2014; 15: R53https://doi.org/10.1186/gb-2014-15-3-r53
- Successful application of whole genome sequencing in a medical genetics clinic.J Pediatr Genet. 2017; 6: 61-76https://doi.org/10.1055/s-0036-1593968
- Sequence to medical phenotypes: a framework for interpretation of human whole genome DNA sequence data.PLoS Genet. 2015; 11e1005496https://doi.org/10.1371/journal.pgen.1005496
- AnnotSV and knotAnnotSV: a web server for human structural variations annotations, ranking and analysis.Nucleic Acids Res. 2021; 49: W21-W28https://doi.org/10.1093/nar/gkab402
- Next-generation diagnostics and disease-gene discovery with the Exomiser.Nat Protoc. 2015; 10: 2004-2015https://doi.org/10.1038/nprot.2015.124
- Alternative transcripts in variant interpretation: the potential for missed diagnoses and misdiagnoses.Genet Med. 2020; 22: 1269-1275https://doi.org/10.1038/s41436-020-0781-x
- Heterozygous variants in MYBPC1 are associated with an expanded neuromuscular phenotype beyond arthrogryposis.Hum Mutat. 2019; 40: 1115-1126https://doi.org/10.1002/humu.23760
- Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations.Genet Med. 2021; 23 (Published correction appears in Genet Med. 2021;23(10):2016. https://doi.org/10.1038/s41436-021-01232-8): 1922-1932
- Rare deleterious de novo missense variants in Rnf2/Ring2 are associated with a neurodevelopmental disorder with unique clinical features.Hum Mol Genet. 2021; 30: 1283-1292https://doi.org/10.1093/hmg/ddab110
- The microRNA processor DROSHA is a candidate gene for a severe progressive neurological disorder.Hum Mol Genet. 2022; 31: 2934-2950https://doi.org/10.1093/hmg/ddac085
- Exome sequencing and whole genome sequencing for the detection of copy number variation.Expert Rev Mol Diagn. 2015; 15: 1023-1032https://doi.org/10.1586/14737159.2015.1053467
- Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders.Genet Med. 2018; 20: 1216-1223https://doi.org/10.1038/gim.2017.246
Article info
Publication history
Published online: December 04, 2022
Accepted:
December 1,
2022
Received in revised form:
November 28,
2022
Received:
August 2,
2022
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
