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Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort.
Dias, Kerith-Rae; Shrestha, Rupendra; Schofield, Deborah; Evans, Carey-Anne; O'Heir, Emily; Zhu, Ying; Zhang, Futao; Standen, Krystle; Weisburd, Ben; Stenton, Sarah L; Sanchis-Juan, Alba; Brand, Harrison; Talkowski, Michael E; Ma, Alan; Ghedia, Sondy; Wilson, Meredith; Sandaradura, Sarah A; Smith, Janine; Kamien, Benjamin; Turner, Anne; Bakshi, Madhura; Adès, Lesley C; Mowat, David; Regan, Matthew; McGillivray, George; Savarirayan, Ravi; White, Susan M; Tan, Tiong Yang; Stark, Zornitza; Brown, Natasha J; Pérez-Jurado, Luis A; Krzesinski, Emma; Hunter, Matthew F; Akesson, Lauren; Fennell, Andrew Paul; Yeung, Alison; Boughtwood, Tiffany; Ewans, Lisa J; Kerkhof, Jennifer; Lucas, Christopher; Carey, Louise; French, Hugh; Rapadas, Melissa; Stevanovski, Igor; Deveson, Ira W; Cliffe, Corrina; Elakis, George; Kirk, Edwin P; Dudding-Byth, Tracy; Fletcher, Janice.
Affiliation
  • 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
  • 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
  • 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 Sc
  • 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, Universit
  • 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.
Genet Med ; 26(5): 101076, 2024 05.
Article in En | MEDLINE | ID: mdl-38258669
ABSTRACT

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.
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Full text: 1 Database: MEDLINE Main subject: Exome / Exome Sequencing / Intellectual Disability Type of study: Diagnostic_studies / Health_economic_evaluation Limits: Child / Child, preschool / Female / Humans / Male Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2024 Type: Article Affiliation country: Australia
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Full text: 1 Database: MEDLINE Main subject: Exome / Exome Sequencing / Intellectual Disability Type of study: Diagnostic_studies / Health_economic_evaluation Limits: Child / Child, preschool / Female / Humans / Male Language: En Journal: Genet Med Journal subject: GENETICA MEDICA Year: 2024 Type: Article Affiliation country: Australia