Ask any parent whose child has a serious health condition or birth defect “What is the value of a diagnosis?” and they will tell you that an answer is worth everything. When a child presents with an undiagnosed condition, they may undergo multiple genetic tests in search of an answer. When those tests come back negative, it can be frustrating for both the family and doctor. Exome Sequencing, a genetic test that analyzes the coding portion of a person’s genome, often provides a diagnosis in cases where previous testing has not. Having a diagnosis can bring an end to the costly and emotionally draining diagnostic odyssey these families face and allow doctors to tailor medical care specifically to the patient.
Would something like exome sequencing be able to provide answers?
Exome sequencing is a genetic test that examines DNA sequence changes in all 22,000 genes in the genome, so it may find a genetic cause that targeted panels and other tests have missed. Statistics vary depending on who is being tested. When analysis is limited to certain symptoms and severity, the detection rate is higher than if the criteria are broader. In those born with birth defects and/or with neurodevelopmental disorders, such as epilepsy or intellectual impairment, exome sequencing finds a genetic cause in 29% to 58% of cases.1-7 More importantly, studies have shown it changes how health is managed in 21% to 49% of cases.1, 8, 9 So, yes, exome sequencing can help end that diagnostic uncertainty many families face.
What exactly is exome sequencing and how does it work?
Each gene provides instructions for something the body needs, like a recipe. The gene’s message is conveyed via its DNA sequence. There are many small differences in DNA sequence from one person to another. Most sequence variation is normal. It either has no effect or contributes to a person’s unique attributes and abilities. Occasionally, a variation in the sequence impacts the gene’s ability to convey its message properly. If a gene doesn’t work properly because there is a change, or variation, in its sequence, it can cause health and/or developmental issues. The entire collection of a person’s genes and other genetic material is referred to as our genome. It is estimated that humans have over 22,000 genes packaged in 46 chromosomes. If a gene is a recipe, the genome is the entire recipe box. (You can learn more about genes at https://www.genome.gov/18016863/a-brief-guide-to-genomics/.)
Genes are comprised of both exons and introns, segments of genes which perform distinct functions. Exons code for proteins while introns are noncoding sections which interrupt the sequences. Exome sequencing analyzes the exons where approximately 85% of the disease-causing variations are found. Simply put, exome sequencing is a test that looks at all of the gene variants in the exons, and identifies variants that are known or highly likely to be involved in the symptoms.
If exome sequencing can test over 22,000 genes, why use targeted or other genetic testing first?
There are several reasons your doctor or genetic counselor may not start with exome testing. It is a common mistake to think that since exome testing looks at all the genes, it can do it all. Each genetic test has its benefits and limitations. Your doctor or genetic counselor will factor in the benefits and limitations of each test type in the context of your clinical situation, using practice guidelines when available.
One of the limitations of exome sequencing is that it cannot detect all types of genetic variation. If a disease is commonly caused by a variation that exome sequencing cannot detect, it is typical to start with a targeted genetic test that may provide a definitive result. In addition, the exome analysis may be of lesser quality than the targeted test. Further, there are parts of the exome that may not be examined as closely under exome sequencing as they are in targeted testing.
When a child presents with an undiagnosed condition, we know that parents and providers are looking for answers. We encourage families and their healthcare providers to carefully research tests like exome sequencing, discuss what they can and cannot reveal, as well as the risks and benefits. Don’t hesitate to ask questions of the laboratory that is being considered. Together, these resources will allow everyone to make an educated and informed decision and help find the answers they need.
To learn more about Quest’s new Exome offering, visit QuestExome.com.
1. Iglesias A, Anyane-Yeboa K, Wynn J, et al. The usefulness of whole-exome sequencing in routine clinical practice. Genet Med. 2014;16:922-931. doi: 10.1038/gim.2014.58
2. 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
3. Retterer K, Scuffins J, Schmidt D, et al. Assessing copy number from exome sequencing and exome array CGH based on CNV spectrum in a large clinical cohort. Genet Med. 2015;17:623-629. doi: 10.1038/gim.2014.160
4. Stark Z, Tan TY, Chong B, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med. 2016;18:1090-1096. doi: 10.1038/gim.2016.1
5. 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:e173438. doi: 10.1001/jamapediatrics.2017.3438
6. Vissers L, van Nimwegen KJM, Schieving JH, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19:1055-1063. doi: 10.1038/gim.2017.1 doi: 10.1038/ejhg.2016.146
7. Trujillano D, Bertoli-Avella AM, Kumar Kandaswami K, et al. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet. 2017;25:176-182. doi: 10.1126/scitranslmed.3010076
8. 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;6:265ra168. doi: 10.1126/scitranslmed.3010076
9. Tan TY, Dillon OJ, Stark Z, et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr. 2017;171:855-862. doi: 10.1001/jamapediatrics.2017.1755