Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort.

Autor:	Dias KR; Neuroscience Research Australia, Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia., Shrestha R; Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia., Schofield D; Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia., Evans CA; Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., O'Heir E; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Zhu Y; Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia; The Genetics of Learning Disability Service, Waratah, NSW, Australia., Zhang F; Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Standen K; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Weisburd B; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Stenton SL; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Sanchis-Juan A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Brand H; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Talkowski ME; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Ma A; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia; Specialty of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia., Ghedia S; Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School, Royal North Shore Hospital, Sydney, NSW, Australia., Wilson M; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia., Sandaradura SA; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia; Disciplines of Child and Adolescent Health and Genetic Medicine, University of Sydney, Sydney, NSW 2050, Australia., Smith J; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia; Specialty of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia., Kamien B; Genetic Services of Western Australia, Perth, WA, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia., Turner A; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia., Bakshi M; Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia., Adès LC; Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia; Disciplines of Child and Adolescent Health and Genetic Medicine, University of Sydney, Sydney, NSW 2050, Australia., Mowat D; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Discipline of Paediatrics & Child Health, Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia., Regan M; Monash Genetics, Monash Health, Melbourne, VIC, Australia., McGillivray G; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., Savarirayan R; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., White SM; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Tan TY; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Stark Z; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia., Brown NJ; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Pérez-Jurado LA; Genetics Unit, Universitat Pompeu Fabra, Institut Hospital del Mar d'Investigacions Mediques (IMIM), Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; Women's and Children's Hospital, South Australian Health and Medical Research Institute & University of Adelaide, Adelaide, SA, Australia., Krzesinski E; Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia., Hunter MF; Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia., Akesson L; Melbourne Pathology, Melbourne, VIC, Australia; Department of Pathology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia., Fennell AP; Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia., Yeung A; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Boughtwood T; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia., Ewans LJ; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Discipline of Paediatrics & Child Health, Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, University of New South Wales Sydney, Sydney, NSW, Australia., Kerkhof J; Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada., Lucas C; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Carey L; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., French H; Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia., Rapadas M; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, University of New South Wales Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW, Australia., Stevanovski I; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, University of New South Wales Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW, Australia., Deveson IW; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, University of New South Wales Sydney, Sydney, NSW, Australia; Centre for Population Genomics, Garvan Institute of Medical Research and Murdoch Children's Research Institute, Sydney, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia., Cliffe C; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Elakis G; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Kirk EP; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia; Discipline of Paediatrics & Child Health, Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia., Dudding-Byth T; The Genetics of Learning Disability Service, Waratah, NSW, Australia., Fletcher J; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Walsh R; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., Corbett MA; Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia., Kroes T; Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia., Gecz J; Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia., Meldrum C; State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia., Cliffe S; State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia., Wall M; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., Lunke S; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia., North K; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia; Global Alliance for Genomics and Health, Toronto, ON, Canada., Amor DJ; Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia., Field M; The Genetics of Learning Disability Service, Waratah, NSW, Australia., Sadikovic B; Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada., Buckley MF; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia., O'Donnell-Luria A; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA., Roscioli T; Neuroscience Research Australia, Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia. Electronic address: tony.roscioli@health.nsw.gov.au.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2024 May; Vol. 26 (5), pp. 101076. Date of Electronic Publication: 2024 Jan 19.
DOI:	10.1016/j.gim.2024.101076
Abstrakt:	Purpose: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. Methods: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. Results: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. Conclusion: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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