Diagnostic yield of genome sequencing after non-diagnostic exome sequencing: a retrospective review of 118 cases at a single institution
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction:
Exome sequencing (ES) and genome sequencing (GS) are increasingly recognized as first-tier diagnostic tests for patients with complex disease. While both assays have similar applications, they differ in coverage, read depth, and cost. Although comprehensive genomic testing evolves toward increasing affordability, ES remains less expensive than GS. Despite these differences, the estimated diagnostic yield for GS is 1-10% higher than that of ES. This study reviews patients from a single tertiary institution who underwent GS following non-diagnostic ES over two years, aiming to evaluate the utility of a stepwise testing approach.
Methods:
A comprehensive report was generated from the clinical genomics department's EPIC system to identify individuals who had undergone GS after non-diagnostic ES between January 1, 2022, and December 31, 2023. A retrospective chart review identified 118 patients. GS results were deemed positive if a new pathogenic or likely pathogenic variant(s) was identified that provided at least a partial explanation for the patient's phenotype. Demographic, phenotypic, and test report data were abstracted. Phenotypes were further categorized as “neurological disorder,” “neurological disorder with non-neurologic phenotype,” “specific neurological disorder,” or “non-neurologic disorder.”
Results:
Of the 118 patients, 8 (6.8%) had new diagnostic findings on GS after a negative or inconclusive ES. Among these, 7 patients had “neurological disorders with non-neurologic phenotypes,” and 1 had a “non-neurologic disorder.” Notably, 5 of the 8 patients were under 18 years old at the time of GS. The average time between ES and GS was similar across GS result categories; those with new positive GS results had an average of 2.16 years between tests, compared to 2.99 years for negative results, 3.22 years for VUS, and 2.17 years for incidental findings.
Of these 8 new findings, 2 were repeat expansions, 1 was a mitochondrial variant, and 5 were coding variants, with 2 of these coding variants reclassified from variant of uncertain significance (VUS) to likely pathogenic. None of the 3 coding variants newly identified in GS were in GC rich or repetitive regions. Two out of these 3 coding variants were in genes described in published literature before initiation of ES. The other of those three coding variants resided in a gene that was associated with a relevant phenotype in a paper released the same month as the patient’s ES report.
Conclusion:
These findings emphasize the technical differences between ES and GS, particularly the ability of certain GS data pipelines to detect repeat expansions on top of structural and mitochondrial variants usually missed by ES approaches. They also highlight the value of gene discovery over time. However, the additional yield of GS following ES appears to be less than 10%. Challenges in non-coding variant interpretation and establishing gene-disease associations remain significant barriers to improving the diagnostic yield of GS.
Exome sequencing (ES) and genome sequencing (GS) are increasingly recognized as first-tier diagnostic tests for patients with complex disease. While both assays have similar applications, they differ in coverage, read depth, and cost. Although comprehensive genomic testing evolves toward increasing affordability, ES remains less expensive than GS. Despite these differences, the estimated diagnostic yield for GS is 1-10% higher than that of ES. This study reviews patients from a single tertiary institution who underwent GS following non-diagnostic ES over two years, aiming to evaluate the utility of a stepwise testing approach.
Methods:
A comprehensive report was generated from the clinical genomics department's EPIC system to identify individuals who had undergone GS after non-diagnostic ES between January 1, 2022, and December 31, 2023. A retrospective chart review identified 118 patients. GS results were deemed positive if a new pathogenic or likely pathogenic variant(s) was identified that provided at least a partial explanation for the patient's phenotype. Demographic, phenotypic, and test report data were abstracted. Phenotypes were further categorized as “neurological disorder,” “neurological disorder with non-neurologic phenotype,” “specific neurological disorder,” or “non-neurologic disorder.”
Results:
Of the 118 patients, 8 (6.8%) had new diagnostic findings on GS after a negative or inconclusive ES. Among these, 7 patients had “neurological disorders with non-neurologic phenotypes,” and 1 had a “non-neurologic disorder.” Notably, 5 of the 8 patients were under 18 years old at the time of GS. The average time between ES and GS was similar across GS result categories; those with new positive GS results had an average of 2.16 years between tests, compared to 2.99 years for negative results, 3.22 years for VUS, and 2.17 years for incidental findings.
Of these 8 new findings, 2 were repeat expansions, 1 was a mitochondrial variant, and 5 were coding variants, with 2 of these coding variants reclassified from variant of uncertain significance (VUS) to likely pathogenic. None of the 3 coding variants newly identified in GS were in GC rich or repetitive regions. Two out of these 3 coding variants were in genes described in published literature before initiation of ES. The other of those three coding variants resided in a gene that was associated with a relevant phenotype in a paper released the same month as the patient’s ES report.
Conclusion:
These findings emphasize the technical differences between ES and GS, particularly the ability of certain GS data pipelines to detect repeat expansions on top of structural and mitochondrial variants usually missed by ES approaches. They also highlight the value of gene discovery over time. However, the additional yield of GS following ES appears to be less than 10%. Challenges in non-coding variant interpretation and establishing gene-disease associations remain significant barriers to improving the diagnostic yield of GS.