Insights with

Whole-genome sequencing outperforms analysis of genomic variants with greater capabilities to analyze diverse variant classes among all clinical genomic testing methods. Prior to WGS, it would not be uncommon to require multiple test methodologies to uncover the diverse types of variants (shown below) associated with genetic disease.

With one test, clinicians and their lab partners have a single workflow with capabilities to identify broad classes of variants in human disease.

Limited capabilities


*Variant detection may vary depending on particular laboratory and performance limits of validated variant types.
NGS = next-generation sequencing

CNVs can be an important variant class in neurodevelopmental disorders10 and WGS captures CNVs with greater resolution than other testing methodologies such as CMA.1,10,12,14,15,19,20 While WES and WGS are both next generation sequencing methods used to address broad variation in the genome, WGS offers a number of superior capabilities to detect variant classes superior to WES, such as structural variants. Many rare disease diagnoses found with WGS would have been missed by WES, including those caused by repeat expansions or mutations in noncoding regions.3-6,11-13

Nearly 10% of molecularly diagnosed patients have multiple pathogenic variants

Significant diversity in pathogenic variation underlying genetic diseases.
Multiple variant types identified in 5-12% of molecularly diagnosed diseases.16-18
Demonstrates value of comprehensive approach.

Variant Distribution

(n=699 patients)18

WGS testing performed in the Illumina Clinical Services Laboratory represents individuals enrolled in disease-specific clinical trials or as part of philanthropic efforts. As such, the percentage represented here may not be typical of that seen in a standard laboratory. This data is based on 699 total cases.

In two of the largest studies of patients suspected of a genetic disease, WGS outperformed WES

of diagnoses were in regions outside of typical exome capabilities (noncoding regions, short tandem repeats, mitochondrial variants, structural variants at base pair level). An additional 2% of diagnoses were in coding variants within regions of low-coverage with exome sequencing.11

of diagnoses using WGS within the Undiagnosed Disease Network had a prior normal exome sequencing result.13

  1. Lionel AC, Costain G, Monfared N, et al. 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(4):435-443. doi:10.1038/gim.2017.119
  2. Gross AM, Ajay SS, Rajan V, et al. Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease. Genet Med. 2019;21(5):1121-1130. doi:10.1038/s41436-018-0295-y
  3. Dolzhenko E, van Vugt JJFA, Shaw RJ, et al. Detection of long repeat expansions from PCR-free whole-genome sequence data. Genome Res. 2017;27(11):1895-1903. doi:10.1101/gr.225672.117
  4. Alfares A, Aloraini T, Subaie LA, et al. Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing. Genet Med. 2018;20(11):1328-1333. doi:10.1038/gim.2018.41
  5. van Kuilenburg ABP, Tarailo-Graovac M, Richmond PA, et al. Glutaminase Deficiency Caused by Short Tandem Repeat Expansion in GLS. N Engl J Med. 2019;380(15):1433-1441. doi:10.1056/NEJMoa1806627
  6. Ibañez K, Polke J, Hagelstrom RT, et al. Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study. Lancet Neurol. 2022;21(3):234-245. doi:10.1016/S1474-4422(21)00462-2
  7. Chen X, Schulz-Trieglaff O, Shaw R, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics. 2016;32(8):1220-1222. doi:10.1093/bioinformatics/btv710
  8. Carss KJ, Arno G, Erwood M, et al. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017;100(1):75-90. doi:10.1016/j.ajhg.2016.12.003
  9. Chen X, Sanchis-Juan A, French CE, et al. Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. Genet Med. 2020;22(5):945-953. doi:10.1038/s41436-020-0754-0
  10. Mollon J, Almasy L, Jacquemont S, Glahn DC. The contribution of copy number variants to psychiatric symptoms and cognitive ability. Mol Psychiatry. 2023 Apr;28(4):1480-1493. doi: 10.1038/s41380-023-01978-4. Epub 2023 Feb 3. PMID: 36737482; PMCID: PMC10213133.
  11. 100,000 Genomes Project Pilot Investigators, Smedley D, Smith KR, et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report. N Engl J Med. 2021;385(20):1868-1880. doi:10.1056/NEJMoa2035790
  12. Belkadi A, Bolze A, Itan Y, et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc Natl Acad Sci U S A. 2015;112(17):5473-5478. doi:10.1073/pnas.1418631112
  13. Splinter K, Adams DR, Bacino CA, et al. Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease. N Engl J Med. 2018;379(22):2131-2139. doi:10.1056/NEJMoa1714458
  14. Stavropoulos DJ, Merico D, Jobling R, et al. Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine. NPJ Genom Med. 2016;1:15012. doi:10.1038/npjgenmed.2015.12
  15. Turro E, Astle WJ, Megy K, et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature. 2020;583(7814):96-102. doi:10.1038/s41586-020-2434-2
  16. Posey et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. New England Journal of Medicine. 2017.
  17. Scoccia et al. Clinical whole-genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico. NPJ Genome Med. 2019.
  18. Data on file at Illumina Clinical Services Laboratory; patient cohort of 699.
  19. Lindstrand A, Eisfeldt J, Pettersson M, et al. From cytogenetics to cytogenomics: whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability. Genome Med. 2019;11(1):68. doi:10.1186/s13073-019-0675-1
  20. Trost B, Walker S, Wang Z, et al. A Comprehensive Workflow for Read Depth-Based Identification of Copy-Number Variation from Whole-Genome Sequence Data. Am J Hum Genet. 2018;102(1):142-155. doi:10.1016/j.ajhg.2017.12.007