A Decade of Rapid Exome Sequencing at a Tertiary Care Center
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
Exome sequencing is a genetic test that sequences all the protein-coding, exonic regions of the DNA and is commonly used to identify pathogenic variants in patients with suspected genetic disorders. Compared to traditional exome sequencing, rapid exome sequencing (rES) is optimized to deliver results within a significantly faster turnaround time enabling prompt decision-making for patients in critical conditions. This study aims to describe the ongoing experience of ordering rES for critically ill patients at Johns Hopkins Hospital. A multidisciplinary committee comprising providers from Genetics, Genetic Counseling, Neonatology, and Pathology, evaluated cases from June 2014 onwards to determine patient eligibility for rES. As of November 2022, this decision-making process was integrated into the routine clinical workflow with testing decisions made directly by providers. We aim to highlight the continued effectiveness of rES in delivering timely diagnoses that can inform clinical decision-making and patient outcomes.
Methods:
Patients who underwent rES at the Johns Hopkins Hospital were identified through genetic testing laboratory provider portals and internal databases. This included all cases reported from October 2014 to June 2024. Data was retrospectively collected from EPIC electronic health records using a standardized spreadsheet. The diagnostic yield was the primary outcome of this study, defined as the presence of pathogenic or likely pathogenic variant(s) that explain the patient’s clinical presentation. The secondary outcomes assessed included demographics, turnaround times, and the impact of rES on clinical care.
Results:
A total of 195 patients underwent rES within this timeframe with an overall diagnostic rate of 31% (60/195). Variants of uncertain significance were reported in 35% (68/195) of patients and 34% (67/195) had a negative result. Trio testing was pursued in most cases (78%). The largest age group at the time of sample collection was neonates (<1 month, 41%), followed by infants (1–12 months, 26%), with smaller groups of toddlers (1–3 years, 6%), children (3–10 years, 10%), adolescents (10–19 years, 9%), and adults (>19 years, 8%). The diagnostic rate ranged from 31-42% across age categories except for the adolescent group where only 1 proband out of 17 had a positive result (6%). The diagnostic yield for patients approved by the multidisciplinary committee for rES was 31% (21/67). Following the transition to routine rES testing without committee oversight, the yield remained similar at 30% (39/128). A two-proportion z-test indicated no statistically significant difference in diagnostic rates between the two periods (z = 0.126, p = 0.897). On average, it took 12 days (median = 7 days, IQR = 7-13 days) from when the sample was collected until the report was issued.
Conclusion:
Over the past decade, rES has provided essential diagnostic insights for critically ill patients at our center. Importantly, the transition to more routine use of rES did not diminish its diagnostic integrity despite the significant increase in the volume of tests ordered after November 2022. While diagnostic rates varied across age groups, the high overall yield underscores the broad utility of this testing across pediatric and adult patient populations. For most cases, chromosomal microarray and mitochondrial DNA analysis were ordered concurrently with rES. Further research could explore the utility of concurrent testing methods to assess the full diagnostic potential in cases where rES alone is nondiagnostic and whether specific clinical indications are associated with higher diagnostic yields. Overall, our experience with rES illustrates that it is a vital tool in critical care settings, and it can be effectively integrated into existing clinical workflows for the timely diagnosis of genetic conditions.
Exome sequencing is a genetic test that sequences all the protein-coding, exonic regions of the DNA and is commonly used to identify pathogenic variants in patients with suspected genetic disorders. Compared to traditional exome sequencing, rapid exome sequencing (rES) is optimized to deliver results within a significantly faster turnaround time enabling prompt decision-making for patients in critical conditions. This study aims to describe the ongoing experience of ordering rES for critically ill patients at Johns Hopkins Hospital. A multidisciplinary committee comprising providers from Genetics, Genetic Counseling, Neonatology, and Pathology, evaluated cases from June 2014 onwards to determine patient eligibility for rES. As of November 2022, this decision-making process was integrated into the routine clinical workflow with testing decisions made directly by providers. We aim to highlight the continued effectiveness of rES in delivering timely diagnoses that can inform clinical decision-making and patient outcomes.
Methods:
Patients who underwent rES at the Johns Hopkins Hospital were identified through genetic testing laboratory provider portals and internal databases. This included all cases reported from October 2014 to June 2024. Data was retrospectively collected from EPIC electronic health records using a standardized spreadsheet. The diagnostic yield was the primary outcome of this study, defined as the presence of pathogenic or likely pathogenic variant(s) that explain the patient’s clinical presentation. The secondary outcomes assessed included demographics, turnaround times, and the impact of rES on clinical care.
Results:
A total of 195 patients underwent rES within this timeframe with an overall diagnostic rate of 31% (60/195). Variants of uncertain significance were reported in 35% (68/195) of patients and 34% (67/195) had a negative result. Trio testing was pursued in most cases (78%). The largest age group at the time of sample collection was neonates (<1 month, 41%), followed by infants (1–12 months, 26%), with smaller groups of toddlers (1–3 years, 6%), children (3–10 years, 10%), adolescents (10–19 years, 9%), and adults (>19 years, 8%). The diagnostic rate ranged from 31-42% across age categories except for the adolescent group where only 1 proband out of 17 had a positive result (6%). The diagnostic yield for patients approved by the multidisciplinary committee for rES was 31% (21/67). Following the transition to routine rES testing without committee oversight, the yield remained similar at 30% (39/128). A two-proportion z-test indicated no statistically significant difference in diagnostic rates between the two periods (z = 0.126, p = 0.897). On average, it took 12 days (median = 7 days, IQR = 7-13 days) from when the sample was collected until the report was issued.
Conclusion:
Over the past decade, rES has provided essential diagnostic insights for critically ill patients at our center. Importantly, the transition to more routine use of rES did not diminish its diagnostic integrity despite the significant increase in the volume of tests ordered after November 2022. While diagnostic rates varied across age groups, the high overall yield underscores the broad utility of this testing across pediatric and adult patient populations. For most cases, chromosomal microarray and mitochondrial DNA analysis were ordered concurrently with rES. Further research could explore the utility of concurrent testing methods to assess the full diagnostic potential in cases where rES alone is nondiagnostic and whether specific clinical indications are associated with higher diagnostic yields. Overall, our experience with rES illustrates that it is a vital tool in critical care settings, and it can be effectively integrated into existing clinical workflows for the timely diagnosis of genetic conditions.