Original Research Article

A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders

Received:
Accepted:
Published online:

Abstract

Purpose:

To prospectively evaluate the diagnostic and clinical utility of singleton whole-exome sequencing (WES) as a first-tier test in infants with suspected monogenic disease.

Methods:

Singleton WES was performed as a first-tier sequencing test in infants recruited from a single pediatric tertiary center. This occurred in parallel with standard investigations, including single- or multigene panel sequencing when clinically indicated. The diagnosis rate, clinical utility, and impact on management of singleton WES were evaluated.

Results:

Of 80 enrolled infants, 46 received a molecular genetic diagnosis through singleton WES (57.5%) compared with 11 (13.75%) who underwent standard investigations in the same patient group. Clinical management changed following exome diagnosis in 15 of 46 diagnosed participants (32.6%). Twelve relatives received a genetic diagnosis following cascade testing, and 28 couples were identified as being at high risk of recurrence in future pregnancies.

Conclusions:

This prospective study provides strong evidence for increased diagnostic and clinical utility of singleton WES as a first-tier sequencing test for infants with a suspected monogenic disorder. Singleton WES outperformed standard care in terms of diagnosis rate and the benefits of a diagnosis, namely, impact on management of the child and clarification of reproductive risks for the extended family in a timely manner.

Genet Med 18 11, 1090–1096.

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Acknowledgements

This study was funded by the members of the Melbourne Genomics Health Alliance and the State Government of Victoria (Department of Health and Human Services). We thank the patients and families for participating in this study. We are grateful to Rodney Hunt, Amanda Moody, David Tingay, John Mills, Michael Stewart, Anastasia Pellicano, Leah Hickey, Julia Gunn, Margaret Moran, Mark Mackay, Avihu Boneh, and Cathy Quinlan for referring patients to the study; Kate Pope for genetic counseling support; Nessie Mupfeki for data-management support; and Harriet Dashnow, Gayle Phillip, Anthony Marty, and Andrew Lonie for bioinformatics and database-development support. We also acknowledge the Melbourne Genomics Health Alliance Steering Group, the Clinical Genomics and Bioinformatics Advisory Group, and the Clinical Genomics Advisory Group for establishing the systems and standards applied in this study.

Author information

Affiliations

  1. Murdoch Childrens Research Institute, Melbourne, Australia

    • Zornitza Stark
    • , Tiong Y. Tan
    • , Belinda Chong
    • , Gemma R. Brett
    • , Patrick Yap
    • , Maie Walsh
    • , Alison Yeung
    • , Heidi Peters
    • , Dylan Mordaunt
    • , Shannon Cowie
    • , David J. Amor
    • , Ravi Savarirayan
    • , George McGillivray
    • , Lilian Downie
    • , Paul G. Ekert
    • , Christiane Theda
    • , Joy Yaplito-Lee
    • , Monique M. Ryan
    • , Richard J. Leventer
    • , Emma Creed
    • , Ivan Macciocca
    • , Katrina M. Bell
    • , Alicia Oshlack
    • , Simon Sadedin
    • , Natalie Thorne
    •  & Susan M White
  2. University of Melbourne, Melbourne, Australia

    • Tiong Y. Tan
    • , Heidi Peters
    • , Dylan Mordaunt
    • , David J. Amor
    • , Ravi Savarirayan
    • , Paul G. Ekert
    • , Christiane Theda
    • , Monique M. Ryan
    • , Richard J. Leventer
    • , Alicia Oshlack
    • , Peter Georgeson
    • , Charlotte Anderson
    • , Natalie Thorne
    • , Clara Gaff
    •  & Susan M White
  3. Royal Women’s Hospital, Melbourne, Australia

    • Christiane Theda
  4. Royal Children’s Hospital, Melbourne, Australia

    • Heidi Peters
    • , Dylan Mordaunt
    • , Joy Yaplito-Lee
    • , Monique M. Ryan
    •  & Richard J. Leventer
  5. Melbourne Genomics Health Alliance, Melbourne, Australia

    • Gemma R. Brett
    • , Emma Creed
    • , Natalie Thorne
    •  & Clara Gaff
  6. Royal Melbourne Hospital, Melbourne, Australia

    • Paul A. James
    •  & Emma Creed

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Contributions

The last two authors contributed equally to this work.

Corresponding author

Correspondence to Susan M White.

Supplementary information

Word documents

  1. 1.

    Supplementary Table S1