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Understanding
Whole Exome Sequencing

A Comprehensive First-Tier Test for Diagnosing Rare Disease and Unexplained Symptoms

Rare Disease is Often Unanswered. We Want to Help Change That.

Many rare genetic diseases – especially with pediatric patients – present nonspecific or overlapping clinical features (e.g. global developmental delay, intellectual disability), making the differential diagnosis challenging without genetic testing. Unfortunately, many patients undergo traditional genetic testing methods that look at only a few genes, missing the underlying genetic cause. This can lead to frequent misdiagnosis and delaying care.

The Consequences of Delayed Diagnosis

Up to 1 in 10

Americans have a rare disease1,2

Up to 85%

of rare diseases are genetic or have a genetic component2-5

5-7

years is the average time to reach a diagnosis1,6-8

30%

of pediatric patients with a rare disease will die before their 5th birthday9

33%

of critically ill infants in the NICU with a suspected genetic disease will die before getting their diagnosis10,11

With Whole Exome Sequencing That Could All Change

Guidelines recommend Whole Exome Sequencing (WES), as a comprehensive first-tier approach that uses next-generation sequencing to analyze the coding regions of a person’s genome – known as the exome – where approximately 85%12 of disease-causing variants are located.12 This makes WES a highly efficient and focused method to offering greater diagnostic potential and resolution by uncovering the genetic cause of complex, atypical or unexplained conditions. Increasingly recognized as a standard of care, we have the opportunity to help bring closure to their diagnostic odyssey.

Revealing Genetic Disorders Where They Are Most Common

Traditional genetic testing methods used in isolation – such as multi-gene panels have limitations in variant detection, or lack broad exome coverage, often leading to a lower likelihood† of finding a diagnosis. Inconclusive results from initial tests may prompt additional genetic tests, adding complexity, time, and cost to the diagnostic workup, utilizing more resources and extending the diagnostic journey.

†Based on diagnostic yield.

Compared to traditional* testing methods which has limited coverage of the genome, WES can evaluate where 85% of disease-causing variants exist in the genome.
  • Higher Diagnostic Yield13-19**
  • Faster Diagnosis23***
  • Improved Clinical Management13,14,17,24
  • Reduced Medical Costs26

*Chromosomal microarray (CMA) and targeted panels. **Varies across cohorts of disease. ***Avoids repeated genetic testing with traditional methods.

Disease Causing Variant Coverage
Disease Causing Variant Coverage Chart
With pediatric and adult patients, WES is used to help determine the etiology of a patient’s symptoms when a genetic condition is suspected in nonacute clinical presentation.
Higher
Diagnostic Yield

WES has demonstrated a diagnostic yield ranging from 24% to 35%16-19 in outpatient pediatric cohorts across different clinical indications. Compared to traditional testing methods (12% to 24%),20-22 WES provides a significantly higher likelihood of finding a diagnosis.

Faster Diagnosis

With its superior diagnostic yield, WES promises fasters answers, with an average time to result in weeks versus 4 to 5 years with traditional testing methods.23

Improved Clinical
Management

WES has been shown to impact clinical management in 41% to 52% of outpatients pediatric a with a positive diagnosis, when implemented early in the diagnostic pathway.14,17,24

Reduced
Medical Cost

With broad existing payer coverage27, patients can undergo less testing and fewer physician visits resulting in reduced resource utilization and lowering the cost of the diagnosis and care management.26

In acute clinical cases when time is critical, Rapid Whole Exome Sequencing (rWES) can be utilized to help quickly identify genetic causes of a patient’s symptoms. Unlike standard WES, rWES delivers results in days not weeks-enabling faster diagnosis and care decisions.
Higher
Diagnostic Yield

rWES has demonstrated a diagnostic yield range of 28% – 37%13-15 in NICU patient cohorts across different clinical indications. Compared to traditional testing methods (~10%)25,28,29 rWES provides a higher likelihood of finding a diagnosis.

Faster
Diagnosis

Approximately one-third of critically ill infants die before receiving a diagnosis and offering rWES can lead to a shorter time (days versus weeks) to diagnosis and inform care faster.

Improved Clinical
Management

rWES has shown to change clinical management in almost 60% of infants in the ICU receiving a positive result.16

Reduced
Medical Cost

Undiagnosed NICU patients have higher resource utilization and longer hospital stays, the cost of which is absorbed by the hospital or the patient’s family. Finding a diagnosis faster with comprehensive genomic testing like rWES, can support cost management by minimizing hospital stays and avoiding unnecessary procedures.

Indications for WES and rWES include

Society Recommended Indications

  • Congenital Anomalies (such as cardiac, skeletal, and genitourinary anomalies)
  • Developmental Delays
  • Epilepsy
  • Intellectual Disability
  • Neurodevelopmental Disorders

Additional Indications

  • Autism Spectrum Disorder
  • Cardiac Arrest
  • Cerebral Palsy
  • Extensive Differential Diagnosis
  • Failure to Thrive
  • Hypotonia
  • Immunodeficiencies
  • Metabolic Disturbances
  • Neuromuscular Disorders
  • Previous Genetic Testing Uninformative
  • Prolonged and/or Recurrent Hospital Stays
  • Respiratory Insufficiency at Term
  • Vision and Hearing Loss
Recommended by Medical Societies

The promise of WGS to improve diagnosis and management of rare disease is being validated in clinical practice and recognized by medical societies across the world as a first or second-tier diagnostic test for rare disease.

AAP

American Academy of Pediatrics recommends genome or exome sequencing as a first or second-tier test. (See Clinical Report)

  • Indications: Global Developmental Delay | Intellectual Disability | Congenital Anomalies

AES

American Epilepsy Society (AES) recommends genome or exome sequencing as a first-tier test. (See Guideline)

  • Indications: Unexplained Epilepsy

ACMG

American College of Medical Genetics and Genomics (ACMG) recommends genome or exome sequencing as a first or second-tier test. (See Guideline)

  • Indications: Developmental Delay | Intellectual Disability | Congenital Anomalies

NSGC

National Society of Genetic Counselors (NSGC) recommends genome or exome sequencing as a first-tier test. (See Guideline)

  • Indications: Unexplained Epilepsy

IPCHiP

International Precision Child Health Partnership (IPCHiP) recommends rapid genome or rapid exome sequencing as a first-line option. (See Consensus)

  • Indication: NICU patients with Unexplained Hypotonia

Global Medical Society

  • European Society of Human Genetics (See Recommendation)
  • Royal Australasian College of Physicians Paediatrics and Child Health Division (See Guidance)
  • CMDA Chinese Medical Doctor Association, Medical Genetics Branch​ (See Consensus)

Compared to Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES) is more accessible. For patients who cannot access WGS due to availability or insurance coverage, WES is considered the next best option for comprehensive genetic testing.

WGS can sequence most of the genome, analyzing both coding and non-coding regions; whereas WES only analyzes the coding region. Comparatively, WGS has a slightly higher diagnostic yield compared to WES because it can analyze areas of the genome and variant types that WES cannot – this gives patients a slightly better advantage to finding a genetic cause to their symptoms. Both tests, however, are great options to help understand the genetic etiology of a patient with rare disease or unexplained symptoms.
WGS – Learn More
WES
Diagnostic Yield
(Across NICU and Outpatient Cohorts)
27% to 43%
24% to 37%
Analyzes Coding Region
(85% of disease-causing variants exist in the coding region)
Yes
Yes
Analyzes Non-Coding Regions
Yes
No
Single Nucleotide Variant (SNV)
Yes
Yes
Copy Number Variant (CNV)
Yes
Limited
Mitochondrial DNA
Yes
No – Separate Test Needed
Short Tandem Repeats (STR)
Yes
No
Regions of Homozygosity (ROH)
Yes
No
Uniparental Disomy (UPD)
Yes
No
Rapid Available
Yes
Yes
  1. Global Genes. Allies in Rare Disease. https://globalgenes.org/rare-disease-facts/. Accessed June 28, 2025.
  2. Bick D, Jones M, Taylor SL, Taft RJ, Belmont J. Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. J Med Genet. 2019;56(12):783-791. doi:10.1136/jmedgenet-2019-106111
  3. Nguengang Wakap S, Lambert DM, Olry A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165-173. doi:10.1038/s41431-019-0508-0
  4. Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885-892. doi:10.1002/ajmg.a.61124
  5. Tisdale A, Watson M, McCormack C, et al. The IDeaS initiative: pilot study to assess the impact of rare diseases on patients and healthcare systems. Orphanet J Rare Dis. 2021;16(1):429. doi:10.1186/s13023-021-02061-3
  6. Global Commission on Rare Disease. Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease. https://www.globalrarediseasecommission.com/. Accessed June 28, 2025.
  7. Global Genes. Rare Disease Impact Report: Insights from Patients and the Medical Community. https://globalgenes.org/wp-content/uploads/2013/04/ShireReport-1.pdf. Published 2013. Accessed June 28, 2025.
  8. Posada de la Paz M, Taruscio D, Groft SC. Rare diseases epidemiology: update and overview. In: Posada de la Paz M, Taruscio D, Groft SC, eds. Rare Diseases Epidemiology: Update and Overview. 2nd ed. Cham, Switzerland: Springer; 2017:11-18. https://link.springer.com/book/10.1007/978-3-319-67144-4
  9. Dumbuya JS, Zeng C, Deng L, et al. The impact of rare diseases on the quality of life in paediatric patients: current status. Front Public Health. 2025;13:1531583. doi:10.3389/fpubh.2025.1531583
  10. Wojcik MH, Schwartz TS, Yamin I, et al. Genetic disorders and mortality in infancy and early childhood: delayed diagnoses and missed opportunities. Genet Med. 2018;20(11):1396-1404. doi:10.1038/gim.2018.17
  11. Posada de la Paz M, Taruscio D, Groft SC. Rare diseases epidemiology: update and overview. Adv Exp Med Biol. 2017;1031:589-604.
  12. Bamshad M, Ng S, Bigham A, et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet. 2011;12:745-755. doi:10.1038/nrg3031
  13. McDermott H, Sherlaw-Sturrock C, Baptista J, Hartles-Spencer L, Naik S. Rapid exome sequencing in critically ill children impacts acute and long-term management of patients and their families: a retrospective regional evaluation. Eur J Med Genet. 2022;65(9):104571. doi:10.1016/j.ejmg.2022.104571
  14. Meng L, Pammi M, Saronwala A, et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr. 2017;171(12):e173438. doi:10.1001/jamapediatrics.2017.3438
  15. D’Gama AM, Del Rosario MC, Bresnahan MA, Yu TW, Wojcik MH, Agrawal PB. Integrating rapid exome sequencing into NICU clinical care after a pilot research study. NPJ Genom Med. 2022;7(1):51. doi:10.1038/s41525-022-00326-9
  16. Fan X, Zhao S, Yu C, et al. Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature. J Genet Genomics. 2021;48(5):396-402. doi:10.1016/j.jgg.2021.02.008
  17. Scheffer IE, Bennett CA, Gill D, et al. Exome sequencing for patients with developmental and epileptic encephalopathies in clinical practice. Dev Med Child Neurol. 2023;65(1):50-57. doi:10.1111/dmcn.15308
  18. Li Q, Chen Z, Wang J, et al. Molecular diagnostic yield of exome sequencing and chromosomal microarray in short stature: a systematic review and meta-analysis. JAMA Pediatr. 2023;177(11):1149-1157. doi:10.1001/jamapediatrics.2023.3566
  19. Slavotinek A, Rego S, Sahin-Hodoglugil N, et al. Diagnostic yield of pediatric and prenatal exome sequencing in a diverse population. NPJ Genom Med. 2023;8:10. doi:10.1038/s41525-023-00353-0
  20. 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
  21. Costain G, Jobling R, Walker S, et al. Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing. Eur J Hum Genet. 2018;26(5):740-744. doi:10.1038/s41431-018-0114-6
  22. 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
  23. Soden SE, Saunders CJ, Willig LK, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6(265):265ra168. doi:10.1126/scitranslmed.3010076
  24. Graifman JL, Lippa NC, Mulhern MS, Bergner AL, Sands TT. Clinical utility of exome sequencing in a pediatric epilepsy cohort. Epilepsia. 2023;64:986-997. doi:10.1111/epi.17534
  25. Farnaes L, Hildreth A, Sweeney NM, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med. 2018;3:10. doi:10.1038/s41525-018-0049-4
  26. Valencia CA, Husami A, Holle J, et al. Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center’s experience. Front Pediatr. 2015;3:67. doi:10.3389/fped.2015.00067
  27. Data on file.
  28. Olde Keizer RACM, Marouane A, Kerstjens-Frederikse WS, et al. Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder: results of a prospective multicenter clinical utility study in the Netherlands. Eur J Pediatr. 2023;182(6):2683-2692. doi:10.1007/s00431-023-04909-1
  29. Willig LK, Petrikin JE, Smith LD, et al. 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(5):377-387. doi:10.1016/S2213-2600(15)00139-3

The society recommendations, performance characteristics and advantages of Whole Exome Sequencing (WES) or Rapid Whole Exome Sequencing (rWES) presented on this page reflect WES and rWES as a general clinical methodology. They do not specifically recommend Baylor Genetics or represent specific analytical or clinical validation data for the Baylor Genetics WES or rWES tests.

The information provided on this website is intended solely for use by qualified healthcare professionals. It is designed to support, not replace, the clinical judgment of medical practitioners. The content, recommendations, is for informational and educational purposes only and should not be considered as medical advice for patients. Individuals seeking medical guidance should consult a licensed healthcare provider.

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