Clinical impact of genomic testing in patients with suspected monogenic kidney disease.
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ABSTRACT: Purpose
To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.Methods
We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.Results
ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p?ConclusionIn this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.
SUBMITTER: Jayasinghe K
PROVIDER: S-EPMC7790755 | biostudies-literature | 2021 Jan
REPOSITORIES: biostudies-literature
Publications
Clinical impact of genomic testing in patients with suspected monogenic kidney disease.
Jayasinghe Kushani K Stark Zornitza Z Kerr Peter G PG Gaff Clara C Martyn Melissa M Whitlam John J Creighton Belinda B Donaldson Elizabeth E Hunter Matthew M Jarmolowicz Anna A Johnstone Lilian L Krzesinski Emma E Lunke Sebastian S Lynch Elly E Nicholls Kathleen K Patel Chirag C Prawer Yael Y Ryan Jessica J See Emily J EJ Talbot Andrew A Trainer Alison A Tytherleigh Rigan R Valente Giulia G Wallis Mathew M Wardrop Louise L West Kirsty H KH White Susan M SM Wilkins Ella E Mallett Andrew J AJ Quinlan Catherine C
Genetics in medicine : official journal of the American College of Medical Genetics 20200917 1
<h4>Purpose</h4>To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease.<h4>Methods</h4>We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia.<h4>Results</h4>ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age a ...[more]
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Project description:IntroductionRecent advances in genomic technology have allowed better delineation of renal conditions, the identification of new kidney disease genes and subsequent targets for therapy. To date, however, the utility of genomic testing in a clinically ascertained, prospectively recruited kidney disease cohort remains unknown. The aim of this study is to explore the clinical utility and cost-effectiveness of genomic testing within a national cohort of patients with suspected genetic kidney disease who attend multidisciplinary renal genetics clinics.Methods and analysisThis is a prospective observational cohort study performed at 16 centres throughout Australia. Patients will be included if they are referred to one of the multidisciplinary renal genetics clinics and are deemed likely to have a genetic basis to their kidney disease by the multidisciplinary renal genetics team. The expected cohort consists of 360 adult and paediatric patients recruited by December 2018 with ongoing validation cohort of 140 patients who will be recruited until June 2020. The primary outcome will be the proportion of patients who receive a molecular diagnosis via genomic testing (diagnostic rate) compared with usual care. Secondary outcomes will include change in clinical diagnosis following genomic testing, change in clinical management following genomic testing and the cost-effectiveness of genomic testing compared with usual care.Ethics and disseminationThe project has received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. All participants will provide written informed consent for data collection and to undergo clinically relevant genetic/genomic testing. The results of this study will be published in peer-reviewed journals and will also be presented at national and international conferences.
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Project description:Monogenic kidney diseases are involved in up to 15% of end-stage kidney diseases (ESKDs) in adults, and in 70 % of pediatric patients. When these disorders lead to kidney failure (KF), kidney transplantation (KT) is the preferred mode of replacement therapy. KT requires specific considerations depending on the nature of the genetic disorder, the potential oncological risk, the risk of recurrence in the graft, the possibility of specific complications of immunosuppression, and the issue of living donation. The availability of genetic testing should play an increasing role in the evaluation of patients or related living donor candidates before transplantation, relevant for the pretransplantation and posttransplantation management.
| S-EPMC10927483 | biostudies-literature
Project description:ImportanceOptimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.ObjectivesTo investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory.Design, setting, and participantsThis prospective study was part of the Melbourne Genomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.ExposuresAll children underwent singleton WES with targeted phenotype-driven analysis.Main outcomes and measuresThe study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES.ResultsOf 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an incremental cost savings of A$9020 (US$6838) per additional diagnosis (95% CI, A$4304-A$15 404 [US$3263-US$11 678]) compared with the standard diagnostic pathway. Even if WES were performed at the first genetics appointment, there would be an incremental cost savings of A$5461 (US$4140) (95% CI, A$1433-A$10 557 [US$1086- US$8004]) per additional diagnosis compared with the standard diagnostic pathway.Conclusions and relevanceSingleton WES in children with suspected monogenic conditions has high diagnostic yield, and cost-effectiveness is maximized by early application in the diagnostic pathway. Pediatricians should consider early referral of children with undiagnosed syndromes to clinical geneticists.
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