Preliminary Findings from the ABCDEFG (Adult Brain Cohort – Dissecting Efficacy and Efficiency of First-line Genome-wide sequencing) Study
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical-Adult
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Secondary Categories:
- Clinical-Adult & Pediatric
Introduction:
Accurate and efficient diagnosis of neurogenetic disorders (NGD) is required for clinically relevant precision management, including genetically targeted therapies for an increasing number of disorders. Standard genetic testing (SGT) in most adult patients comprises multiple steps in a lengthy and costly diagnostic odyssey. Whole-genome sequencing (WGS) could potentially shorten the diagnostic odyssey and save significant testing costs for many patients by eliminating the need for multiple, separate, and successive genetic tests with a large cumulative cost. However, WGS itself can be costly and interpretation of results is not always straightforward. The ABCDEFG Study aims to determine whether WGS has higher diagnostic utility (DU) and clinical utility than SGT as a first-line test in adults being evaluated for complex neurological disorders (CND). Here, we report preliminary findings of DU and personal utility (PU) from CND patients enrolled to date at the University of California, San Francisco (UCSF).
Methods:
This study is a blind diagnostic intervention crossover randomized controlled trial comparing two first-line testing strategies: 1) WGS, comprising sequencing and analysis of the entire nuclear and mitochondrial genome, including validated copy number and repeat expansion analysis; 2) SGT, comprising testing recommendations made by the medical genetics team at first visit that may include chromosomal microarray, single gene, gene panel, mitochondrial genome and/or whole-exome sequencing. Following an initial evaluation by an adult genetics team, participants undergo both SGT and WGS. Participants are randomized to receive results for either WGS followed by SGT (first-line WGS; study arm 1) or SGT followed by WGS (first-line SGT; study arm 2) over 2 consecutive follow-up appointments. Patients are asked to complete PU surveys prior to testing and upon receiving genetic test results.
Results:
Study recruitment and data collection are ongoing. As of November 2024, 72 adult CND patients have been enrolled at UCSF, with 35 patients in study arm 1 and 37 in study arm 2. Both SGT and WGS results have been obtained for 50 participants thus far, with 10 (20%) receiving genetic diagnoses from WGS and 6 (12%) from SGT. In 2 patients, WGS revealed a highly suspicious variant of uncertain significance, with results of further genetic testing pending. Six (60%) of the diagnoses made on WGS were not identified by SGT, while 2 (33%) diagnoses made on SGT were not identified by WGS.
Of all participants who completed the pre-test PU survey at the time of enrollment (n=71), 69% responded “a lot” when asked how much they believed WGS would provide them with valuable information. Of 39 participants who completed PU surveys following the return of their WGS results, 46% found their results to be helpful in planning for the future, including 75% of those who received a diagnosis (n=8) and 39% of those who did not (n=31). Among 12 participants who completed the PU survey following SGT, more than half (58%) found little to no utility in their SGT results, while 33% did find the results to be helpful.
Conclusion:
Preliminary data from the ABCDEFG Study suggests that WGS as a first-line test may have higher DU than SGT in adults with CND. Additionally, patients tended to report higher PU with WGS than SGT, particularly those who received a diagnosis by WGS. Notably, while more NGD diagnoses were missed by SGT, some were also missed by WGS, underlining the importance of future phenotypic modelling to determine which patients would benefit most and least from each testing strategy. Ongoing enrollment and data collection in the ABCDEFG Study will further delineate the utility of using WGS or SGT as a first-line testing strategy in adults suspected of NGD.
Accurate and efficient diagnosis of neurogenetic disorders (NGD) is required for clinically relevant precision management, including genetically targeted therapies for an increasing number of disorders. Standard genetic testing (SGT) in most adult patients comprises multiple steps in a lengthy and costly diagnostic odyssey. Whole-genome sequencing (WGS) could potentially shorten the diagnostic odyssey and save significant testing costs for many patients by eliminating the need for multiple, separate, and successive genetic tests with a large cumulative cost. However, WGS itself can be costly and interpretation of results is not always straightforward. The ABCDEFG Study aims to determine whether WGS has higher diagnostic utility (DU) and clinical utility than SGT as a first-line test in adults being evaluated for complex neurological disorders (CND). Here, we report preliminary findings of DU and personal utility (PU) from CND patients enrolled to date at the University of California, San Francisco (UCSF).
Methods:
This study is a blind diagnostic intervention crossover randomized controlled trial comparing two first-line testing strategies: 1) WGS, comprising sequencing and analysis of the entire nuclear and mitochondrial genome, including validated copy number and repeat expansion analysis; 2) SGT, comprising testing recommendations made by the medical genetics team at first visit that may include chromosomal microarray, single gene, gene panel, mitochondrial genome and/or whole-exome sequencing. Following an initial evaluation by an adult genetics team, participants undergo both SGT and WGS. Participants are randomized to receive results for either WGS followed by SGT (first-line WGS; study arm 1) or SGT followed by WGS (first-line SGT; study arm 2) over 2 consecutive follow-up appointments. Patients are asked to complete PU surveys prior to testing and upon receiving genetic test results.
Results:
Study recruitment and data collection are ongoing. As of November 2024, 72 adult CND patients have been enrolled at UCSF, with 35 patients in study arm 1 and 37 in study arm 2. Both SGT and WGS results have been obtained for 50 participants thus far, with 10 (20%) receiving genetic diagnoses from WGS and 6 (12%) from SGT. In 2 patients, WGS revealed a highly suspicious variant of uncertain significance, with results of further genetic testing pending. Six (60%) of the diagnoses made on WGS were not identified by SGT, while 2 (33%) diagnoses made on SGT were not identified by WGS.
Of all participants who completed the pre-test PU survey at the time of enrollment (n=71), 69% responded “a lot” when asked how much they believed WGS would provide them with valuable information. Of 39 participants who completed PU surveys following the return of their WGS results, 46% found their results to be helpful in planning for the future, including 75% of those who received a diagnosis (n=8) and 39% of those who did not (n=31). Among 12 participants who completed the PU survey following SGT, more than half (58%) found little to no utility in their SGT results, while 33% did find the results to be helpful.
Conclusion:
Preliminary data from the ABCDEFG Study suggests that WGS as a first-line test may have higher DU than SGT in adults with CND. Additionally, patients tended to report higher PU with WGS than SGT, particularly those who received a diagnosis by WGS. Notably, while more NGD diagnoses were missed by SGT, some were also missed by WGS, underlining the importance of future phenotypic modelling to determine which patients would benefit most and least from each testing strategy. Ongoing enrollment and data collection in the ABCDEFG Study will further delineate the utility of using WGS or SGT as a first-line testing strategy in adults suspected of NGD.