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

Episignature Exome negative Genome sequencing Health economics Intellectual disability

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
19 Jan 2024
Historique:
received: 30 06 2023
revised: 12 01 2024
accepted: 16 01 2024
pubmed: 23 1 2024
medline: 23 1 2024
entrez: 23 1 2024
Statut: aheadofprint

Résumé

Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively. ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. 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. 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.

Identifiants

DOI: 10.1016/j.gim.2024.101076 PMID: 38258669
pubmed: 38258669
pii: S1098-3600(24)00009-1
doi: 10.1016/j.gim.2024.101076
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101076

Informations de copyright

Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of Interest The authors declare no conflicts of interest.

Auteurs

Kerith-Rae 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.

Rupendra Shrestha (R)

Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia.

Deborah Schofield (D)

Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia.

Carey-Anne Evans (CA)

Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Emily O'Heir (E)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Ying 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.

Futao Zhang (F)

Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Krystle Standen (K)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Ben Weisburd (B)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Sarah L Stenton (SL)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Alba Sanchis-Juan (A)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Harrison Brand (H)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Michael E Talkowski (ME)

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.

Alan 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.

Sondy Ghedia (S)

Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School, Royal North Shore Hospital, Sydney, NSW, Australia.

Meredith Wilson (M)

Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia.

Sarah A 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.

Janine 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.

Benjamin Kamien (B)

Genetic Services of Western Australia, Perth, WA, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.

Anne Turner (A)

Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.

Madhura Bakshi (M)

Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.

Lesley C 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.

David 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.

Matthew Regan (M)

Monash Genetics, Monash Health, Melbourne, VIC, Australia.

George McGillivray (G)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.

Ravi 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.

Susan M White (SM)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

Tiong Yang 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.

Zornitza 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.

Natasha J 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.

Luis A 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.

Emma Krzesinski (E)

Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.

Matthew F Hunter (MF)

Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.

Lauren 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.

Andrew Paul Fennell (AP)

Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.

Alison 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.

Tiffany Boughtwood (T)

Murdoch Children's Research Institute, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia.

Lisa J 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.

Jennifer Kerkhof (J)

Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada.

Christopher Lucas (C)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Louise Carey (L)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Hugh French (H)

Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

Melissa 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.

Igor 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.

Ira W 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.

Corrina Cliffe (C)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

George Elakis (G)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Edwin P 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.

Tracy Dudding-Byth (T)

The Genetics of Learning Disability Service, Waratah, NSW, Australia.

Janice Fletcher (J)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Rebecca Walsh (R)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Mark A Corbett (MA)

Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.

Thessa Kroes (T)

Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.

Jozef 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.

Cliff Meldrum (C)

State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia.

Simon Cliffe (S)

State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia.

Meg Wall (M)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.

Sebastian Lunke (S)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.

Kathryn 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.

David J Amor (DJ)

Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.

Michael Field (M)

The Genetics of Learning Disability Service, Waratah, NSW, Australia.

Bekim Sadikovic (B)

Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Michael F Buckley (MF)

New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.

Anne 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.

Tony 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.

Classifications MeSH