What is Whole Exome Sequencing?

WHAT IS WHOLE EXOME SEQUENCING?

Whole Exome Sequencing (WES) is a next-generation sequencing (NGS) technique that sequences all the protein-coding regions (exome) of the genome. While the exome only makes up about 1 – 2% of the genome, it is estimated to contain 85 percent of disease-causing mutations. WES is considered a powerful diagnostic tool used to help identify almost all exonic and adjacent intronic regions.

In November 2021, the American College of Medical Genetics and Genomics (ACMG) published an evidence-based clinical guideline recommending the use of exome and genome sequencing as a first-tier or second-tier test for pediatric patients with congenital anomalies, intellectual disability, and developmental delay.² Making a genetic diagnosis significantly impacts prognosis and medical management, thereby influencing infant mortality and morbidity. Additionally, WES has useful applications in disease treatment, screening, and prenatal diagnosis.³

WHOLE EXOME SEQUENCING AT BAYLOR GENETICS

WES is considered a highly complex test, which requires time and labor for sequencing and interpreting your patient’s data. The clinical workflow for WES includes exome library preparation, sequencing, bioinformatics pipeline, analysis, and interpretation.

Below is a high level overview of the WES workflow:

1. The patient’s DNA is extracted and analyzed. Various sample types are acceptable for WES and include blood, buccal swab, saliva, cultured skin fibroblasts, and extracted DNA.
2. The sequenced data is aligned to the reference genome, GRCh37, and compared to that standardized reference sequence to highlight potentially clinically significant changes.
3. The data is then reviewed by both laboratory directors and the patient’s clinician to determine if any of these highlighted changes could be the cause of an underlying genetic etiology.

Additionally, the patient’s (proband) sequence is also compared to other family members’ sequences if available, to determine any inherited changes. Determining what changes are unique to the patient and what changes are shared with their family members can be extremely useful to find the cause of a genetic condition.

IS WHOLE EXOME SEQUENCING RIGHT FOR MY PATIENT?

Many types of tests are available to analyze disease-causing changes in genes and chromosomes. WES is available to patients who are searching for a diagnosis that may explain their medical issues.⁴ WES technology gives a thorough look at the exome and detects multiple genetic variants (e.g., single nucleotide variants, insertion/deletion, deletions, and duplications) that may lead to rare conditions.

For newborn babies and children in the neonatal and pediatric intensive care units (NICU/PICU), genetic diseases are a major cause of morbidity and mortality. For these critically ill infants and children, Rapid WES (rWES) is an effective and time-saving diagnostic tool. Additionally, WES is particularly helpful for patients with a broad differential diagnosis or for certain congenital conditions with underlying genetic heterogeneity.³ Moreover, many traditional diagnostic methods, even if effective, have longer turnaround times to provide useful information for severely ill patients in an intensive care unit.¹ Another key benefit of WES is that it may avoid time-consuming cascade testing, which can help shorten the diagnostic odyssey.

WHOLE EXOME SEQUENCING OFFERED BY BAYLOR GENETICS

Finding an answer to your patient’s medical condition can be life-altering. Baylor Genetics’ WES is a large-scale genetic test that uses state-of-the-art technology to study a person’s exome to identify the changes/anomalies in the DNA which lead to genetic diseases.

Rapid Whole Exome Sequencing (rWES): Starting turnaround time (TAT) of five days

• Rapid Proband WES (test code 1729)
• Rapid Duo WES (test code 1723)
• Rapid Trio WES (test code 1722)

Whole Exome Sequencing: Starting TAT of six weeks

• Proband WES (test code 1500)
• Duo WES (test code 1603)
• Trio WES (test code 1600)
• Additional Affected Sibling for Trio Whole Exome Sequencing (test code 1602)
• Sequential Trio Whole Exome Sequencing (test code 1601)

Prenatal Whole Exome Sequencing: Starting TAT of three weeks, excluding cell culture time

• Trio WES (test code 1622)

Baylor Genetics also offers WES Reanalysis. This test enables healthcare providers to provide options for reanalysis and interpretation for their patients who had WES performed at Baylor Genetics. Other WES testing options include adding Chromosomal Microarray Analysis or Mitochondrial DNA (mtDNA) Analysis to your patient’s order.

WHAT IS BAYLOR GENETICS’ WHOLE EXOME SEQUENCING DIAGNOSTIC RATE?

Ordering the exome test with a shorter TAT can impact a patient’s health outcome in a significant way, especially for younger patients. 

 Exome sequencing diagnoses in acute care settings are as follows:⁵ 

• Critical (rapid) trio exome – 50.8% 
• Trio exome – 32.4%
• Proband exome – 32.6% 

Critical trio exome provided significantly higher molecular diagnoses in 32/63 infants (50.8%) than proband exome in 58/178 infants (32.6%) and trio exome in 12/37 cases (32.4%) (p=0.011226, Fisher’s test).³   

“For rapid or critical WES, we aim for a turnaround time of five days, which is a very valuable tool in a setting like a NICU or a PICU, where getting a diagnosis faster is needed most,” said Dr. Liesbeth Vossaert, Assistant Clinical Director at Baylor Genetics. 

In addition to rapid test results, we also have flexibility when it comes to sample type. Some of the sample types we accept include saliva, buccal swab, and blood. In just five days, Baylor Genetics’ rWES can possibly alter medical management and greatly impact your patient’s health and well-being. 

FEATURES & BENEFITS OF BAYLOR GENETICS’ WHOLE EXOME SEQUENCING

WES at Baylor Genetics is designed to:

• Find answers for patients with a long list of differential diagnoses
• Find solutions when other genetic testing options have been exhausted
• Direct medical management
• Improve preventive care through the identification of medically actionable results (e.g., secondary findings unrelated to phenotype)
• Discover atypical presentation of diseases
• Expand the phenotype spectrum of diseases by analyzing more patients who have defects in the same gene

Benefits of WES at Baylor Genetics:

• Comprehensive genetic testing solution
• High sensitivity and specificity
• May help determine the answer to your patient’s medical condition
• With a turnaround time of five days for rWES, a full report can be obtained
• More efficient than single-gene or multi-gene panels for diagnosis of unknown genetic and rare syndromes
• Partnership with the Undiagnosed Diseases Network as its main sequencing core for exome and genome sequencing

Limitations of WES:

• Repeat expansions, mitochondrial DNA variants, and balanced chromosomal rearrangements cannot be detected.
• Since this technology cannot see all genetic changes that may lead to genetic conditions, additional testing may be recommended.

ONE TEST, MORE ANSWERS WITH WHOLE EXOME SEQUENCING

Baylor Genetics believes in transforming the quality of life for patients with rare genetic conditions by offering providers with accurate, accessible, and fast genetic testing. We have been a pioneer in using many genomic tools to further our mission in precision medicine. While diagnosis remains to be one of the greatest challenges in treating genetic and rare conditions, Baylor Genetics’ WES could be the solution for that challenge.

Although this test is relatively new in the clinical setting, Baylor Genetics has been offering WES for over a decade. This single comprehensive test has revolutionized the genetics industry and has aided healthcare providers in making a genetic diagnosis for their patients. The quick turnaround time for WES has shown to make a difference in having the results physicians need to make life-changing decisions, especially for those in the NICU and PICU.

Baylor Genetics is dedicated to research and innovation and WES is just another example of how our team of clinicians are working towards making genetic testing simple, and accessible for physicians and their patients searching for answers about their health.

Learn more about WES.

References:

1. Kelly D. Farwell, Layla Shahmirzadi, Dima El-Khechen, Zöe Powis, Elizabeth C. Chao, Brigette Tippin Davis, Ruth M. Baxter, Wenqi Zeng, Cameron Mroske, Melissa C. Parra, Stephanie K. Gandomi, Ira Lu, Xiang Li, Hong Lu, Hsiao-Mei Lu, David Salvador, David Ruble, Monica Lao, Soren Fischbach, Jennifer Wen, Shela Lee, Aaron Elliott, Charles L.M. Dunlop, Sha Tang, Enhanced utility of family-centered diagnostic exome sequencing with inheritance model–based analysis: results from 500 unselected families with undiagnosed genetic conditions, Genetics in Medicine, Volume 17, Issue 7, 2015, Pages 578-586, ISSN 1098-3600, https://doi.org/10.1038/gim.2014.154.
2. Manickam K, McClain MR, Demmer LA, Biswas S, Kearney HM, Malinowski J, Massingham LJ, Miller D, Yu TW, Hisama FM; ACMG Board of Directors. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1. PMID: 34211152.
3. Rabbani, B., Tekin, M. & Mahdieh, N. The promise of whole-exome sequencing in medical genetics. J Hum Genet 59, 5–15 (2014). https://doi.org/10.1038/jhg.2013.114
4. Śmigiel, R.; Biela, M.; Szmyd, K.; Błoch, M.; Szmida, E.; Skiba, P.; Walczak, A.; Gasperowicz, P.; Kosińska, J.; Rydzanicz, M.; Stawiński, P.; Biernacka, A.; Zielińska, M.; Gołębiowski, W.; Jalowska, A.; Ohia, G.; Głowska, B.; Walas, W.; Królak-Olejnik, B.; Krajewski, P.; Sykut-Cegielska, J.; Sąsiadek, M.M.; Płoski, R. Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit. Clin. Med. 2020, 9, 2220. https://doi.org/10.3390/jcm9072220.
5. Meng L, Pammi M, Saronwala A, Magoulas P, Ghazi AR, Vetrini F, Zhang J, He W, Dharmadhikari AV, Qu C, Ward P, Braxton A, Narayanan S, Ge X, Tokita MJ, Santiago-Sim T, Dai H, Chiang T, Smith H, Azamian MS, Robak L, Bostwick BL, Schaaf CP, Potocki L, Scaglia F, Bacino CA, Hanchard NA, Wangler MF, Scott D, Brown C, Hu J, Belmont JW, Burrage LC, Graham BH, Sutton VR, Craigen WJ, Plon SE, Lupski JR, Beaudet AL, Gibbs RA, Muzny DM, Miller MJ, Wang X, Leduc MS, Xiao R, Liu P, Shaw C, Walkiewicz M, Bi W, Xia F, Lee B, Eng CM, Yang Y, Lalani SR. Use of Exome Sequencing for Infants in Intensive Care Units: Ascertainment of Severe Single-Gene Disorders and Effect on Medical Management. JAMA Pediatr. 2017 Dec 4;171(12):e173438. doi: 10.1001/jamapediatrics.2017.3438. Epub 2017 Dec 4. PMID: 28973083; PMCID: PMC6359927.