Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Lisa J Ewans; Deborah Schofield; Rupendra Shrestha; Ying Zhu; Velimir Gayevskiy; Kevin Ying; Corrina Walsh; Eric Lee; Edwin P Kirk; Alison Colley; Carolyn Ellaway; Anne Turner; David Mowat; Lisa Worgan; Mary-Louise Freckmann; Michelle Lipke; Rani Sachdev; David Miller; Michael Field; Marcel E Dinger; Michael F Buckley; Mark J Cowley; Tony Roscioli

doi:10.1038/gim.2018.39

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders

Genet Med. 2018 Dec;20(12):1564-1574. doi: 10.1038/gim.2018.39. Epub 2018 Mar 29.

Authors

Lisa J Ewans^{1

2}, Deborah Schofield^{3

4

5}, Rupendra Shrestha⁴, Ying Zhu^{6

7}, Velimir Gayevskiy³, Kevin Ying³, Corrina Walsh⁷, Eric Lee⁷, Edwin P Kirk^{7

8

9}, Alison Colley¹⁰, Carolyn Ellaway^{8

11}, Anne Turner^{8

9}, David Mowat^{8

9}, Lisa Worgan¹⁰, Mary-Louise Freckmann^{8

9}, Michelle Lipke^{8

12}, Rani Sachdev^{8

9}, David Miller³, Michael Field⁶, Marcel E Dinger^{13

3}, Michael F Buckley⁷, Mark J Cowley^{13

3}, Tony Roscioli^{7

8

14}

Affiliations

¹ St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia. l.ewans@garvan.org.au.
² Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. l.ewans@garvan.org.au.
³ Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
⁴ Faculty of Pharmacy, Charles Perkins Centre, University of Sydney, Sydney, New South Wales, Australia.
⁵ Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.
⁶ The Genetics of Learning Disability Service, Waratah, New South Wales, Australia.
⁷ Randwick Genetics, NSW Health Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia.
⁸ Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, New South Wales, Australia.
⁹ School of Women's and Children's Health, University of New South Wales, Sydney, New South Wales, Australia.
¹⁰ Clinical Genetics Department, Liverpool Hospital, Liverpool, New South Wales, Australia.
¹¹ Disciplines of Child and Adolescent Health and Genetic Medicine, University of Sydney, New South Wales, Australia.
¹² Lady Cilento Children's Hospital, Brisbane, Queensland, Australia.
¹³ St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales, Australia.
¹⁴ NeuRA and Prince of Wales Clinical School, University of New South Wales, Kensington, Australia, New South Wales.

PMID: 29595814
DOI: 10.1038/gim.2018.39

Abstract

Purpose: Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway.

Methods: WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID).

Results: Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis.

Conclusion: Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.

Keywords: Mendelian; cost-effectiveness; diagnosis; exome; genomics.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Computational Biology
Cost-Benefit Analysis / economics
Exome / genetics*
Exome Sequencing / economics
Exome Sequencing / trends*
Female
Genetic Diseases, Inborn / diagnosis
Genetic Diseases, Inborn / economics
Genetic Diseases, Inborn / genetics*
Genetic Testing / economics
Genetic Testing / trends*
Humans
Intellectual Disability / diagnosis
Intellectual Disability / genetics*
Intellectual Disability / pathology
Male
Phenotype