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

Kerith-Rae Dias¹, Rupendra Shrestha², Deborah Schofield², Carey-Anne Evans³, Emily O'Heir⁴, Ying Zhu⁵, Futao Zhang³, Krystle Standen⁶, Ben Weisburd⁴, Sarah L Stenton⁴, Alba Sanchis-Juan⁴, Harrison Brand⁴, Michael E Talkowski⁴, Alan Ma⁷, Sondy Ghedia⁸, Meredith Wilson⁹, Sarah A Sandaradura¹⁰, Janine Smith⁷, Benjamin Kamien¹¹, Anne Turner¹², Madhura Bakshi¹³, Lesley C Adès¹⁰, David Mowat¹⁴, Matthew Regan¹⁵, George McGillivray¹⁶, Ravi Savarirayan¹⁷, Susan M White¹⁸, Tiong Yang Tan¹⁷, Zornitza Stark¹⁹, Natasha J Brown¹⁷, Luis A Pérez-Jurado²⁰, Emma Krzesinski²¹, Matthew F Hunter²¹, Lauren Akesson²², Andrew Paul Fennell²¹, Alison Yeung¹⁷, Tiffany Boughtwood²³, Lisa J Ewans²⁴, Jennifer Kerkhof²⁵, Christopher Lucas⁶, Louise Carey⁶, Hugh French²⁶, Melissa Rapadas²⁷, Igor Stevanovski²⁷, Ira W Deveson²⁸, Corrina Cliffe⁶, George Elakis⁶, Edwin P Kirk²⁹, Tracy Dudding-Byth³⁰, Janice Fletcher⁶, Rebecca Walsh⁶, Mark A Corbett³¹, Thessa Kroes³¹, Jozef Gecz³², Cliff Meldrum³³, Simon Cliffe³³, Meg Wall¹⁶, Sebastian Lunke¹⁶, Kathryn North³⁴, David J Amor³⁵, Michael Field³⁰, Bekim Sadikovic³⁶, Michael F Buckley⁶, Anne O'Donnell-Luria³⁷, Tony Roscioli³⁸

Affiliations

¹ Neuroscience Research Australia, Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
² Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia.
³ Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁵ 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.
⁶ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷ 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.
⁸ Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School, Royal North Shore Hospital, Sydney, NSW, Australia.
⁹ Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia.
¹⁰ 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.
¹¹ Genetic Services of Western Australia, Perth, WA, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
¹² Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
¹³ Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.
¹⁴ 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.
¹⁵ Monash Genetics, Monash Health, Melbourne, VIC, Australia.
¹⁶ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁷ 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.
¹⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
¹⁹ 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.
²⁰ 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.
²¹ Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
²² Melbourne Pathology, Melbourne, VIC, Australia; Department of Pathology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.
²³ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia.
²⁴ 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.
²⁵ Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada.
²⁶ Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁷ 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.
²⁸ 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.
²⁹ 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.
³⁰ The Genetics of Learning Disability Service, Waratah, NSW, Australia.
³¹ Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
³² Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
³³ State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia.
³⁴ 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.
³⁵ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
³⁶ Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
³⁷ 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.
³⁸ 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.

PMID: 38258669
PMCID: PMC11786952
DOI: 10.1016/j.gim.2024.101076

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

Kerith-Rae Dias et al. Genet Med. 2024 May.

. 2024 May;26(5):101076.

doi: 10.1016/j.gim.2024.101076. Epub 2024 Jan 19.

Authors

Affiliations

¹ Neuroscience Research Australia, Sydney, NSW, Australia; Prince of Wales Clinical School, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia.
² Centre for Economic Impacts of Genomic Medicine, Macquarie Business School, Macquarie University, Sydney, NSW, Australia.
³ Neuroscience Research Australia, Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁴ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
⁵ 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.
⁶ New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
⁷ 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.
⁸ Department of Clinical Genetics, Royal North Shore Hospital, Sydney, NSW, Australia; Northern Clinical School, Royal North Shore Hospital, Sydney, NSW, Australia.
⁹ Department of Clinical Genetics, Children's Hospital at Westmead, Sydney Children's Hospital Network, Sydney, NSW, Australia.
¹⁰ 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.
¹¹ Genetic Services of Western Australia, Perth, WA, Australia; School of Paediatrics and Child Health, University of Western Australia, Perth, WA, Australia.
¹² Centre for Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
¹³ Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia.
¹⁴ 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.
¹⁵ Monash Genetics, Monash Health, Melbourne, VIC, Australia.
¹⁶ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
¹⁷ 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.
¹⁸ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
¹⁹ 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.
²⁰ 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.
²¹ Monash Genetics, Monash Health, Melbourne, VIC, Australia; Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
²² Melbourne Pathology, Melbourne, VIC, Australia; Department of Pathology, The Royal Melbourne Hospital, Melbourne, VIC, Australia; Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia.
²³ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Australian Genomics, Melbourne, VIC, Australia.
²⁴ 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.
²⁵ Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada.
²⁶ Department of Medical Genomics, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
²⁷ 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.
²⁸ 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.
²⁹ 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.
³⁰ The Genetics of Learning Disability Service, Waratah, NSW, Australia.
³¹ Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
³² Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia; South Australian Health and Medical Research Institute, Adelaide, SA, Australia.
³³ State Wide Service, New South Wales Health Pathology, Sydney, NSW, Australia.
³⁴ 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.
³⁵ Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia.
³⁶ Verspeeten Clinical Genome Centre London Health Sciences Centre, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
³⁷ 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.
³⁸ 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.

PMID: 38258669
PMCID: PMC11786952
DOI: 10.1016/j.gim.2024.101076

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.

Keywords: Episignature; Exome negative; Genome sequencing; Health economics; Intellectual disability.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Figures

**Figure 1.. ID Flagship study.**
74 trios with molecularly undiagnosed ID investigated using ES (74 trios), GS (32 trios), EpiSign (32 probands) and LRS (16 probands). The overall ES/GS diagnostic yield is 69% (51/74) with 31% (23/74) unresolved. ID, intellectual disability; ES, exome sequencing, GS, genome sequencing; LRS, long read sequencing.

**Figure 2.. Concordance between GS and episignature findings.**
A. A Kleefstra syndrome episignature in proband 62 was concordant to the finding of a duplication in *EHMT1* using GS. B. A Beckwith-Weidemann syndrome with IC2 episignature in proband 44 and detection of a *de novo* heterozygous partial out of frame tandem duplication (NM_015335.5, exons 5 – 16 of 31) of *MED13L* using GS might be related by a yet unknown mechanism.

See this image and copyright information in PMC

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Miscellaneous