Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis.

Ofer Barnea, Ph.D. reports from the European Journal of Human Genetics

Published: 22.08.2022

Original article: https://rdcu.be/cT6PR

With the cost drop and increased ease of Whole Genome Sequencing techniques, the scientific world had transitioned to sequence the entire 3.1B long code that is the genome instead of a biased targeted sequencing test or even a Whole Exome Sequencing test (WES). The additional information gained on the entire gene-body (exons and introns included) and moreover, non-coding regulatory regions pose the greater potential to discover new diseases causing SNVs, SVs, and CNVs missed by the WES or other targeted approaches.

For the clinical genetic world, when required to provide clinically actionable answers at the end of the diagnosis path, the question of cost-effectiveness of the either targeted/WES or WGS approaches comes into play. Although the improvement of utilizing WGS over WES to diagnose Mendelian disorders is scientifically understandable, the key measurement missing to convince medical providers as well as payors such as insurance companies and government health ministries is the delta gained in diagnostic yield.

A recent paper in the European Journal of Human Genetics put this notion to the test. They found that out of 91 patients across 64 families with undiagnosed Mendelian disorders, in New South Wales, Australia, 13 of the 38 unresolved families (34%) were diagnosed when using WGS instead of WES. Previous WES analyses failed to resolve these cases due to previously unknown gene-disease association (23%), insufficient sequencing coverage (31%), the variant prioritization pipeline (15%), and the bioinformatics pipeline (23%), or CNV detection (8%).

As scientific knowledge accumulates both the analysis capabilities improve, hence periodical re-analysis of old unresolved cases might provide a genetical resolution. In this study WES reanalysis, approximately 2 years following the original WES analysis, identifies the genetic cause of the disease in 7 of the 13 families (54%) that were resolved by WGS alone. 

When accounting for this, reanalyzing WES-negative families, by updated WES analysis tools increased the diagnostic yield by 18% and the sequential WGS on the still unresolved families increase the diagnostic yield by an additional 19%. This is compared to the 34% increase by WGS analysis from the beginning.

What is better as an initial test WES or WGS? Comparing the diagnostic yield over these 64 families revealed a 9% increase in diagnostic yield by using WGS at the outset rather than contemporary WES analysis.

Explanations for WGS diagnoses missed by WES. A Bar chart comparing the grouping of explanations for missed WES diagnoses made by WGS in blue for prior (original) WES and red for WES reanalysis. Visualization of the proportion of missed WES diagnoses based on the reason for prior WES (B) and WES reanalysis (C).

If an early genetic test had been done before, WES reanalysis will be lowest on the cost but the maximizing diagnostic yield will be achieved by performing WGS. In the case no prior genetic test has been done, the most cost-effective strategy for maximal diagnoses is to perform an initial WGS. The WGS test cost may still result in downstream health and social cost savings, which, over a lifetime, may dwarf the overall individual healthcare costs[1]

The authors concluded that WGS is the optimal genomic test choice to maximize the diagnostic yield in Mendelian disorders across all clinical scenarios, however, it is not the lowest in cost.

Geneyx Analysis platform allows the clinical geneticist to easily employ WES or WGS analysis and periodically reanalysis in a seamless matter, keeping up to date with the latest scientific knowledge base and toolsets.


[1] Impacts of genomics on the health and social costs of intellectual disability | Journal of Medical Genetics (bmj.com)

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Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis.

What is better as an initial test WES or WGS? A recent paper in the European Journal of Human Genetics put this notion to the test. They found that out of 91 patients across 64 families with undiagnosed Mendelian disorders, in New South Wales, Australia, 13 of the 38 unresolved families (34%) were diagnosed when using WGS instead of WES. Previous WES analyses failed to resolve these cases due to previously unknown gene-disease association (23%), insufficient sequencing coverage (31%), the variant prioritization pipeline (15%), and the bioinformatics pipeline (23%), or CNV detection (8%). Comparing the diagnostic yield over these 64 families revealed a 9% increase in diagnostic yield by using WGS at the outset rather than contemporary WES analysis. As scientific knowledge accumulates both the analysis capabilities improve, hence periodical re-analysis of old unresolved cases might provide a genetical resolution.

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Whole exome and genome sequencing in mendelian disorders: a diagnostic and health economic analysis.

What is better as an initial test WES or WGS? A recent paper in the European Journal of Human Genetics put this notion to the test. They found that out of 91 patients across 64 families with undiagnosed Mendelian disorders, in New South Wales, Australia, 13 of the 38 unresolved families (34%) were diagnosed when using WGS instead of WES. Previous WES analyses failed to resolve these cases due to previously unknown gene-disease association (23%), insufficient sequencing coverage (31%), the variant prioritization pipeline (15%), and the bioinformatics pipeline (23%), or CNV detection (8%). Comparing the diagnostic yield over these 64 families revealed a 9% increase in diagnostic yield by using WGS at the outset rather than contemporary WES analysis. As scientific knowledge accumulates both the analysis capabilities improve, hence periodical re-analysis of old unresolved cases might provide a genetical resolution.

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With more than 300 accounts and close to 200,000 cases analyzed, Geneyx Analysis is continuing to receive global adoption in clinical and academic settings. One differentiating feature that advances this adoption is our patient-centric vision. Our vision at Geneyx is to improve diagnostic rates and turnaround times. To do so requires implementing new and innovative features, and since the last release of Geneyx v5.8, there have been many exciting updates that are worth noting.

Improving Case Diagnosis with Geneyx Analysis

Geneyx Analysis is becoming adopted globally as a flexible and innovative solution for rare disease interpretation and has been shown to dramatically improve diagnostic yields. One of the many features that contribute to this capability is the utilization of a novel phenotype-dependent algorithm, which finds relevant associations between gene and phenotype ontologies. This feature is utilized by researchers and clinical geneticists to identify candidate variants and investigate literature for novel biomedical findings.

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In the field of next-generation sequencing, one essential feature is automation. Automation can enable increased scalability and faster turnaround times with improved diagnoses. If applied correctly, this not only benefits the clinical environment but also the field of precision medicine. And although many companies advertise this, Geneyx Analysis actually delivers it.

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