The Similarities, Differences, and Importance of Whole Genome and Whole Exome Sequencing

Whole Genome and Whole Exome Sequencing are highly important in diagnosing rare diseases. They are considerably complex, and major health plans are considering covering these tests for certain patient groups. Download this white paper to learn more about the history, evolution, and current state of WGS and WES.

WES and WGS sequencing are extremely important in rare disease diagnostics, however complex. Health plans are considering covering these services and careviso is here to help.

Laboratory test results influence most clinical decisions that impact patient care. One facet of laboratory testing that has exploded in the last few decades is molecular genetic testing, due to new technological discoveries and the relative reduction in cost.

Decades ago, genes could only be sequenced one at a time using a technique called Sanger sequencing, named after Fredrick Sanger who developed the technique. While this was a major scientific breakthrough at the time, it was expensive and time consuming.

In the early 2000s, Next Generation Sequencing (NGS) became clinically available, which scaled the process to test for multiple genes simultaneously. This also drastically reduced the cost and turnaround time.

Currently, Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) are considered some of the most comprehensive molecular tests available. The protein-coding portion of a gene is called an exon, which consists of about 1% of a person’s entire genome.

• Whole Exome Sequencing (WES) sequences only the exons of the genome.
• Whole Genome Sequencing (WGS) sequences the entire genome of a patient.

The impact of WES and WGS on treatment is dependent upon the clinical scenario. The literature has reported WES may provide a genetic diagnosis that contradicts a clinical diagnosis based on symptoms alone.

For example, a patient was incorrectly diagnosed with chronic inflammatory demyelinating polyneuropathy, but WES gave a diagnosis of Spastic Ataxia of Charlevoix-Saguenay. This changed the medical management where immunotherapy was deemed unnecessary.

Another patient had a diagnosis of hereditary spastic paraplegia, but WES diagnosed the patient with dopa-responsive dystonia. The patient was able to walk without assistance after dopa therapy was initiated.
   
WES and WGS can provide the vital information physicians need to properly diagnose and care for patients with rare diseases. There are about 6,000 genetic conditions. Many of these can be diagnosed by symptoms alone, and a positive “routine” genetic test is confirmatory.

However, there are many children (and families) whose symptoms do not fit a specific diagnosis. These families are on a “diagnostic odyssey,” where they have appointments with multiple specialists over several years with no diagnosis. This can cause a heavy financial and emotional burden to the family. WES and WGS may possibly deliver the answers these families have desperately desired.

The diagnostic yield of WES and WGS can vary, depending on the symptoms of the patient.

• A review that included 37 articles from the literature reported a 42% diagnostic rate for WES for patients presenting with intellectual disability.
• Another review that included results from over 32,000 patients from 103 studies found the overall diagnostic yield of exome sequencing to be 23.7%. It was noted that the highest yield was in patients with early onset seizures and intellectual disability.
• Finally, a meta-analysis from 23 studies with data from 1567 critically ill infants reported WES and WGS had a combined diagnostic yield of 50%.

Professional medical societies like the American College of Medical Genetics and Genomics (ACMG) have created Policy Statements to serve as educational resources for clinicians. Just within the last two years, ACMG published Statements about germline (hereditary) genetic testing, DNA-based screening for personal and population health, and how to report secondary findings (incidental findings that were resulted on genetic testing).

Furthermore, other professional medical societies have published Practice Guidelines about WES and WGS including the American College of Obstetricians and Gynecologists, American Society of Human Genetics, and National Society of Genetic Counselors, among others.
           
The utility of WES and WGS has been proven for specific clinical scenarios and should impact patient care. Different payors may have variations in their standards for coverage. Depending on the payor, criteria for coverage of WES/WGS testing may include:

• Strong evidence that a patient’s symptoms ar edue to a genetic cause but not matched to a well-defined syndrome.
• Symptoms impact multiple organ systems.
• Symptoms may also include global developmental delay, moderate intellectual disability, or autism spectrum disorder, among other neurological features.

Some payors require pre- and post-test genetic counseling by a qualified healthcare professional for coverage.

Our DNA is the blueprint our bodies need to grow and develop properly. Changes in this living blueprint can cause serious health problems. When there is no clear cause of a likely genetic condition, WES and WGS may offer a diagnosis that is critical for patient care. Health insurance payors may have specific policies in place that allow for coverage of WES and WGS.

For example, UHC recently announced that beginning March 1st 2023, they will consider covering WGS/WES in certain situations such as a patient who has a nonspecific diagnosis with global developmental delay, intellectual disability, autism, multiple anomalies, significant hearing loss, an inborn error of metabolism, or neuromuscular disease or other features not attributed to a syndrome. WES and WGS are tools clinicians may use to diagnose a rare condition.

careviso has the platform and expertise to assist clinicians through the access, financial transparency, and preauthorization process so families can possibly get a diagnosis.

Fortunately, careviso (formerly known as CMT Solutions) is an independent patient access and transparency company that specializes in prior authorization services for WES and WGS. Their proprietary online platform called seeQer streamlines the financial transparency and prior authorization process.

It can be time consuming and cumbersome for the medical and/or laboratory staff to determine if a patient’s health plan will potentially cover tests like WES and WGS, and what the financial costs may be for the patient and health plan. careviso and seeQer automates this process, thus improving patient access to WES and WGS when medically necessary and clinically indicated, and answering the questions about cost.

References

Durmaz AA, Karaca E, Demkow U, Toruner G, Schoumans J, Cogulu O. Evolution of genetic techniques: past, present, and beyond. Biomed Res Int. 2015;2015:461524. doi: 10.1155/2015/461524. PMID: 25874212.

https://pubmed.ncbi.nlm.nih.gov/25874212/

Haskell GT, Adams MC, Fan Z, Amin K, Guzman Badillo RJ, Zhou L, Bizon C, Chahin N, Greenwood RS, Milko LV, Shiloh-Malawsky Y, Crooks KR, Strande N, Tennison M, Tilley CR, Brandt A, Wilhelmsen KC, Weck K, Evans JP, Berg JS. Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurol Genet. 2018 Feb 1;4(1):e212. doi: 10.1212/NXG.0000000000000212. PMID: 29417091.

https://pubmed.ncbi.nlm.nih.gov/29417091/

Sánchez-Luquez KY, Carpena MX, Karam SM, Tovo-Rodrigues L. The contribution of whole-exome sequencing to intellectual disability diagnosis and knowledge of underlying molecular mechanisms: A systematic review and meta-analysis. Mutat Res Rev Mutat Res. 2022 Jul-Dec;790:108428. doi: 10.1016/j.mrrev.2022.108428. PMID: 35905832.

https://pubmed.ncbi.nlm.nih.gov/35905832/

Stefanski A, Calle-López Y, Leu C, Pérez-Palma E, Pestana-Knight E, Lal D. Clinical sequencing yield in epilepsy, autism spectrum disorder, and intellectual disability: A systematic review and meta-analysis. Epilepsia. 2021 Jan;62(1):143-151. doi: 10.1111/epi.16755. PMID: 33200402.

https://pubmed.ncbi.nlm.nih.gov/33200402/

Xiao F, Yan K, Tang M, Ji X, Hu L, Yang L, Zhou W. Diagnostic utility of rapid sequencing in critically ill infants: a systematic review and meta-analysis. Expert Rev Mol Diagn. 2022 Aug;22(8):833-840. doi: 10.1080/14737159.2022.2123704. PMID: 36082848.

https://pubmed.ncbi.nlm.nih.gov/36082848/