The role of exome sequencing in childhood interstitial or diffuse lung disease

Suzanna E L Temple^{1

2}, Gladys Ho^{3

4}, Bruce Bennetts^{3

4}, Kirsten Boggs^{5

6

7}, Nada Vidic^{8

5}, David Mowat^{8

7}, John Christodoulou^{4

5

9

10}, André Schultz^{11

12

13}, Thet Gayagay³, Tony Roscioli^{7

14

15}, Ying Zhu¹⁴, Sebastian Lunke^{5

9

10}, David Armstrong^{16

17}, Joanne Harrison^{9

18}, Nitin Kapur^{19

20}, Tim McDonald²¹, Hiran Selvadurai^{4

22}, Andrew Tai^{23

24}, Zornitza Stark^{5

9

10}, Adam Jaffe^{8

25}

Affiliations

¹ Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia. suzanna.lindseytemple@health.nsw.gov.au.
² School of Women's and Children's Health, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia. suzanna.lindseytemple@health.nsw.gov.au.
³ Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁴ Disciplines of Child and Adolescent Health and Genomic Medicine, University of Sydney, Sydney, NSW, Australia.
⁵ Australian Genomics Health Alliance, Melbourne, VIC, Australia.
⁶ Department of Clinical Genetics, Children's Hospital Westmead, Sydney, NSW, Australia.
⁷ Centre for Clinical Genetics, Sydney Children's Hospital Randwick, Sydney, NSW, Australia.
⁸ School of Women's and Children's Health, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia.
⁹ University of Melbourne, Melbourne, VIC, Australia.
¹⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Wal-Yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
¹² Department of Respiratory Medicine, Perth Children's Hospital, Nedlands, WA, Australia.
¹³ Division of Paediatrics, Faculty of Medicine, University of Western Australia, Perth, Australia.
¹⁴ Randwick Genomics Laboratory, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, Australia.
¹⁵ Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia.
¹⁶ Department of Paediatrics, Monash University, Clayton Rd, Clayton, VIC, Australia.
¹⁷ Department of Respiratory and Sleep Medicine, Monash Children's Hospital, Clayton Rd, Clayton, VIC, Australia.
¹⁸ Department of Respiratory and Sleep Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁹ Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia.
²⁰ School of Medicine, University of Queensland, Brisbane, QLD, Australia.
²¹ The Canberra Hospital, Garran, ACT, Australia.
²² Children's Hospital Westmead, Sydney, NSW, Australia.
²³ Paediatric Respiratory and Sleep Department, Women's and Children's Hospital, Adelaide, SA, Australia.
²⁴ Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
²⁵ Department Respiratory and Sleep Medicine, Sydney Children's Hospital, Randwick, NSW, Australia.

PMID: 36085161
PMCID: PMC9463757
DOI: 10.1186/s13023-022-02508-1

The role of exome sequencing in childhood interstitial or diffuse lung disease

Suzanna E L Temple et al. Orphanet J Rare Dis. 2022.

. 2022 Sep 9;17(1):350.

doi: 10.1186/s13023-022-02508-1.

Authors

Affiliations

¹ Department of Clinical Genetics, Liverpool Hospital, Sydney, NSW, Australia. suzanna.lindseytemple@health.nsw.gov.au.
² School of Women's and Children's Health, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia. suzanna.lindseytemple@health.nsw.gov.au.
³ Sydney Genome Diagnostics, Western Sydney Genetics Program, The Children's Hospital at Westmead, Sydney, NSW, Australia.
⁴ Disciplines of Child and Adolescent Health and Genomic Medicine, University of Sydney, Sydney, NSW, Australia.
⁵ Australian Genomics Health Alliance, Melbourne, VIC, Australia.
⁶ Department of Clinical Genetics, Children's Hospital Westmead, Sydney, NSW, Australia.
⁷ Centre for Clinical Genetics, Sydney Children's Hospital Randwick, Sydney, NSW, Australia.
⁸ School of Women's and Children's Health, Faculty of Medicine and Health, UNSW, Sydney, NSW, Australia.
⁹ University of Melbourne, Melbourne, VIC, Australia.
¹⁰ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Wal-Yan Respiratory Research Centre, Telethon Kids Institute, University of Western Australia, Perth, Australia.
¹² Department of Respiratory Medicine, Perth Children's Hospital, Nedlands, WA, Australia.
¹³ Division of Paediatrics, Faculty of Medicine, University of Western Australia, Perth, Australia.
¹⁴ Randwick Genomics Laboratory, NSW Health Pathology, Prince of Wales Hospital, Sydney, NSW, Australia.
¹⁵ Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia.
¹⁶ Department of Paediatrics, Monash University, Clayton Rd, Clayton, VIC, Australia.
¹⁷ Department of Respiratory and Sleep Medicine, Monash Children's Hospital, Clayton Rd, Clayton, VIC, Australia.
¹⁸ Department of Respiratory and Sleep Medicine, The Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁹ Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, Brisbane, QLD, Australia.
²⁰ School of Medicine, University of Queensland, Brisbane, QLD, Australia.
²¹ The Canberra Hospital, Garran, ACT, Australia.
²² Children's Hospital Westmead, Sydney, NSW, Australia.
²³ Paediatric Respiratory and Sleep Department, Women's and Children's Hospital, Adelaide, SA, Australia.
²⁴ Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia.
²⁵ Department Respiratory and Sleep Medicine, Sydney Children's Hospital, Randwick, NSW, Australia.

PMID: 36085161
PMCID: PMC9463757
DOI: 10.1186/s13023-022-02508-1

Abstract

Background: Children's interstitial and diffuse lung disease (chILD) is a complex heterogeneous group of lung disorders. Gene panel approaches have a reported diagnostic yield of ~ 12%. No data currently exist using trio exome sequencing as the standard diagnostic modality. We assessed the diagnostic utility of using trio exome sequencing in chILD. We prospectively enrolled children meeting specified clinical criteria between 2016 and 2020 from 16 Australian hospitals. Exome sequencing was performed with analysis of an initial gene panel followed by trio exome analysis. A subset of critically ill infants underwent ultra-rapid trio exome sequencing as first-line test.

Results: 36 patients [median (range) age 0.34 years (0.02-11.46); 11F] were recruited from multiple States and Territories. Five patients had clinically significant likely pathogenic/pathogenic variants (RARB, RPL15, CTCF, RFXANK, TBX4) and one patient had a variant of uncertain significance (VIP) suspected to contribute to their clinical phenotype, with VIP being a novel gene candidate.

Conclusions: Trio exomes (6/36; 16.7%) had a better diagnostic rate than gene panel (1/36; 2.8%), due to the ability to consider a broader range of underlying conditions. However, the aetiology of chILD in most cases remained undetermined, likely reflecting the interplay between low penetrant genetic and environmental factors.

Keywords: Genetics; Interstitial lung disease; Paediatric lung disease; Paediatrics; Rare lung diseases.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Recruitment for chILDRANZ and number enrolled in trio Whole Exome Sequencing (WES)

See this image and copyright information in PMC

References

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The role of exome sequencing in childhood interstitial or diffuse lung disease

Affiliations

The role of exome sequencing in childhood interstitial or diffuse lung disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

LinkOut - more resources

Full Text Sources

Medical