The Genomic Consultation Service: A clinical service designed to improve patient selection for genome‐wide sequencing in British Columbia

Elliott, Alison M.; Souich, Christèle du; Adam, Shelin; Dragojlovic, Nick; Nelson, Tanya N.; Lehman, Anna; Lynd, Larry D.; Friedman, Jan M.

doi:10.1002/mgg3.410

Cited by 20 publications

(23 citation statements)

References 23 publications

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“…We have described our experience of establishing a multi-disciplinary team format for the application of NGS in a clinical setting, using a prospective ES case series to illustrate the operation and results of this approach. Our findings demonstrate the value of a multidisciplinary evaluation and consensus-based decision-making by a team within a clinical environment, complementing and informing related but distinct experience reported elsewhere such as the Genome Clinic Task Force (Geneva) [6], Genomic Consultation Service (British Columbia) [35], Individualised Medicine Clinic (Mayo) [36] and Undiagnosed Disease Network (NIH) [9]. Here we have shown how this approach can be implemented at a local level within a national health service, the impact of case selection, sequencing strategy and evaluation of results, and the health economics of such a format.…”

Section: Discussionsupporting

confidence: 77%

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

et al. 2019

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Background A multi-disciplinary approach to promote engagement, inform decision-making and support clinicians and patients is increasingly advocated to realise the potential of genome-scale sequencing in the clinic for patient benefit. Here we describe the results of establishing a genomic medicine multi-disciplinary team (GM-MDT) for case selection, processing, interpretation and return of results. Methods We report a consecutive case series of 132 patients (involving 10 medical specialties with 43.2% cases having a neurological disorder) undergoing exome sequencing over a 10-month period following the establishment of the GM-MDT in a UK NHS tertiary referral hospital. The costs of running the MDT are also reported. Results In total 76 cases underwent exome sequencing following triage by the GM-MDT with a clinically reportable molecular diagnosis in 24 (31.6%). GM-MDT composition, operation and rationale for whether to proceed to sequencing are described, together with the health economics (cost per case for the GM-MDT was £399.61), the utility and informativeness of exome sequencing for molecular diagnosis in a range of traits, the impact of choice of sequencing strategy on molecular diagnostic rates and challenge of defining pathogenic variants. In 5 cases (6.6%), an alternative clinical diagnosis was indicated by sequencing results. Examples were also found where findings from initial genetic testing were reconsidered in the light of exome sequencing including TP63 and PRKAG2 (detection of a partial exon deletion and a mosaic missense pathogenic variant respectively); together with tissue-specific mosaicism involving a cytogenetic abnormality following a normal prenatal array comparative genomic hybridization. Conclusions This consecutive case series describes the results and experience of a multidisciplinary team format that was found to promote engagement across specialties and facilitate return of results to the responsible clinicians. Electronic supplementary material The online version of this article (10.1186/s13073-019-0651-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 77%

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

et al. 2019

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“…Although the population studied was ethnically and geographically diverse, our findings may not be generalizable to other patient groups. Most of the children were over the age of 3 at time of testing, which is relevant because it has been reported that both testing decisions and acceptance of living without a diagnosis may be influenced by child's age (Aldridge et al., 2021; Elliott et al., 2018; Li et al., 2016). The model of care provided in CAUSES, with most negative results being provided by telephone, may also influence parents’ perceptions when interviewed several months afterward.…”

Section: Discussionmentioning

confidence: 99%

“…This study took place in the Children's & Women's Health Centre of BC, Vancouver, Canada, the major referral center and only dedicated pediatric and women's hospital in the Province of British Columbia and the Yukon Territory. We recruited parents from a translational research study, CAUSES (Clinical Assessment of the Utility of Sequencing and Evaluation as a Service) (Elliott et al., 2018), which performed trio‐based GWS (either exome or whole genome sequencing) on 500 pediatric patients and their parents, where the child had a suspected, but undiagnosed genetic disorder. At the time of the CAUSES study, GWS was not available clinically.…”

Section: Methodsmentioning

confidence: 99%

After genomic testing results: Parents’ long‐term views

Liang

Adam

Elliott

et al. 2021

Journal of Genetic Counseling

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Many parents are motivated to pursue genome‐wide (exome or genome) sequencing to find a diagnosis for their child with a suspected but undiagnosed genetic condition. However, the impact of the genomic test extends beyond the provision of results and the so‐called ‘diagnostic odyssey’. Our goal was to quantify post‐test decisional regret and characterize long‐term, post‐test experiences and unmet needs of the parents of children with suspected genetic diseases after they had received the results of genome‐wide sequencing. Study participants were parents of children who underwent trio genome‐wide sequencing as part of the CAUSES research study at Children's & Women's Health Centre of British Columbia. About half of the participants received a definite or likely genetic diagnosis after clinical interpretation of the genome‐wide sequencing results. Parents who participated in the current study (n = 121) completed the Decisional Regret Scale four weeks after receiving results. A subset of these parents (n = 32) had semi‐structured interviews a median of 7 months (range 3–20 months) after results disclosure and post‐test genetic counseling. Most parents expressed either no regret or mild regret about having undergone genome‐wide sequencing on both the Decisional Regret Scale and in the interviews. Parents whose children did not receive a genetic diagnosis were slightly more likely to have decisional regret on this quantitative scale. Analysis of transcribed interviews revealed the following major themes: (a) a lack of decisional conflict around having the testing; (b) a lack of decisional regret post‐testing; (c) expressions of both relief and continued uncertainty around the meaning of a genetic diagnosis; (d) expression of initial disappointment and evolving interpretation surrounding a result yielding no genetic diagnosis; and (e) needing time to absorb the test results. Our results suggest that parents need time to absorb the testing results and that long‐term post‐test counseling, including acknowledging feelings of relief, loss, and disappointment, may help parents adapt to the genomic test results and assist families to anticipate and plan for the next steps in their child's medical trajectory, whether or not a diagnosis is found.

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“…The patient cohorts screened for known STR expansions in this study consist of the ES data of 141 trios or quads from the Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) Study [ 25 ] and the WGS data of 160 trios or quads from the Integrated Metabolomics And Genomics In Neurodevelopment (IMAGINE) [ 26 ] or CAUSES Studies. Subjects enrolled in the CAUSES Study were children who were suspected on clinical grounds to have a single gene disorder but in whom conventional testing had not identified a genetic cause.…”

Section: Methodsmentioning

confidence: 99%

“…The PCR-free whole-genome sequencing data of Coriell samples with known short tandem repeat expansions analyzed in the current study can be accessed in the European Genome-phenome Archive repository: https://www.ebi.ac.uk/ega/datasets/EGAD00001003562 [ 10 ]. Individual patient clinical or genomic data from the CAUSES [ 25 ] and IMAGINE [ 26 ] Studies are not available because they are potentially individually identifiable and not consented for public release. Investigators who wish access to the summary data of CAUSES and IMAGINE Studies can contact Dr. Jan Friedman (jmf@bcchr.ca).…”

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confidence: 99%

Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions

et al. 2021

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Background Screening for short tandem repeat (STR) expansions in next-generation sequencing data can enable diagnosis, optimal clinical management/treatment, and accurate genetic counseling of patients with repeat expansion disorders. We aimed to develop an efficient computational workflow for reliable detection of STR expansions in next-generation sequencing data and demonstrate its clinical utility. Methods We characterized the performance of eight STR analysis methods (lobSTR, HipSTR, RepeatSeq, ExpansionHunter, TREDPARSE, GangSTR, STRetch, and exSTRa) on next-generation sequencing datasets of samples with known disease-causing full-mutation STR expansions and genomes simulated to harbor repeat expansions at selected loci and optimized their sensitivity. We then used a machine learning decision tree classifier to identify an optimal combination of methods for full-mutation detection. In Burrows-Wheeler Aligner (BWA)-aligned genomes, the ensemble approach of using ExpansionHunter, STRetch, and exSTRa performed the best (precision = 82%, recall = 100%, F1-score = 90%). We applied this pipeline to screen 301 families of children with suspected genetic disorders. Results We identified 10 individuals with full-mutations in the AR, ATXN1, ATXN8, DMPK, FXN, or HTT disease STR locus in the analyzed families. Additional candidates identified in our analysis include two probands with borderline ATXN2 expansions between the established repeat size range for reduced-penetrance and full-penetrance full-mutation and seven individuals with FMR1 CGG repeats in the intermediate/premutation repeat size range. In 67 probands with a prior negative clinical PCR test for the FMR1, FXN, or DMPK disease STR locus, or the spinocerebellar ataxia disease STR panel, our pipeline did not falsely identify aberrant expansion. We performed clinical PCR tests on seven (out of 10) full-mutation samples identified by our pipeline and confirmed the expansion status in all, showing absolute concordance between our bioinformatics and molecular findings. Conclusions We have successfully demonstrated the application of a well-optimized bioinformatics pipeline that promotes the utility of genome-wide sequencing as a first-tier screening test to detect expansions of known disease STRs. Interrogating clinical next-generation sequencing data for pathogenic STR expansions using our ensemble pipeline can improve diagnostic yield and enhance clinical outcomes for patients with repeat expansion disorders.

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The Genomic Consultation Service: A clinical service designed to improve patient selection for genome‐wide sequencing in British Columbia

Cited by 20 publications

References 23 publications

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

Implementation of a genomic medicine multi-disciplinary team approach for rare disease in the clinical setting: a prospective exome sequencing case series

After genomic testing results: Parents’ long‐term views

Genome-wide sequencing as a first-tier screening test for short tandem repeat expansions

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