Advances in molecular diagnostics offer clinicians more choices than ever when it comes to disease-targeted genetic testing for their patients.¹ However, the amount of options can complicate deciding which test is best for each patient.  Next generation sequencing (NGS)-based clinical genetic tests, such as multi-gene panel testing (MGPT), offer very high base pair coverage to pinpoint a molecular diagnosis in  patients suspected to have a Mendelian disease. However, MGPT may become outdated quickly, particularly with respect to newly characterized disease genes. 

WES can provide an underlying diagnosis in an efficient, cost-effective manner² and incorporates analysis of newly characterized genes. However, it typically offers average base pair coverage at 90-95% at >20X (or lower, in some cases).¹ Recent research digs deeper into this coverage for disease-causing changes (pathogenic variants), to better understand the possibility of WES as a first-tier diagnostic tool for clinicians.
High Coverage is Possible with WESNew research suggests that whole exome sequencing (WES) offers similar base pair coverage to MGPT for Mendelian diseases while also incorporating newly characterized disease genes and novel gene findings.

 Researchers at Ambry Genetics and University of California, Irvine collaborated to look at results from more than 50,000 patients who underwent targeted NGS MGPT at Ambry from 2010 to 2014. Patients were tested for a range of Mendelian disorders such as cancer, heart disease and intellectual disability.

 Results were searched for single nucleotide substitutions and small insertion/deletion events; corresponding nucleotide positions for these were compared against data from 100 randomly-selected patients who underwent clinical WES at Ambry. Coverage at each position was assessed.

 Key Study Results

• 1,533 different pathogenic variants identified on MGPT were included in the comparison, representing 91 genes in 5 disease categories
• Adequate depth for variant detection by WES was observed in 99.7% of pathogenic variants
• A total of 97.3% of the pathogenic variants demonstrated adequate depth for detection across all 100 WES samples
• Among these 100 WES samples, 98% bases were covered at >20X

 To validate study findings, a similar analysis was performed against coverage data from more than 60,000 exomes available through the Exome Aggregation Consortium (ExAC). This confirmed that 98.6% of pathogenic variants demonstrated adequate depth for detection.

 Points for Your Practice

• Average coverage by WES is estimated at 95% overall, but this research shows that coverage exceeds that threshold when restricting to positions where mutations have occurred (?98.5%)
• WES may achieve a similar diagnostic yield as targeted MGPT for inherited disease

 Lead author Holly LaDuca, MS, CGC, Manager of Clinical Data Analytics at Ambry, said, “The results from this study are the first to quantify the risk for false negatives on WES versus MGPT, and demonstrate that disease-causing mutations are unlikely to occur in areas that are not well covered. We hope clinicians find this to be a useful resource in cases where they are contemplating exome sequencing versus panel testing.”

The high level of coverage achieved by WES as reported by this study, coupled with newly characterized disease genes and novel gene findings, demonstrate the major benefits of WES as compared to MGPT for Mendelian diseases.

If cost and turnaround time are comparable or favorable, WES may be an appropriate first-tier option to consider when clinically indicated.

Read the research here.

References

1. Rehm HL. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet. 2013 Apr;14(4):295-300.
2. Stark Z, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med. 2016 Nov;18(11):1090-6.