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

Suzanna E. L. Temple, Gladys Ho, Bruce Bennetts, Kirsten Boggs, Nada Vidic, David Mowat, John Christodoulou, Andre Schultz, Thet Gayagay, Tony Roscioli, Ying Zhu, Sebastian Lunke, David Armstrong, Joanne Harrison, Nitin Kapur, Tim McDonald, Hiran Selvadurai, Andrew Tai, Zornitza Stark, Adam Jaffe

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


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 similar to 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); 11 F] 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.

Original languageEnglish
Article number350
Number of pages9
JournalOrphanet Journal of Rare Diseases
Issue number1
Publication statusPublished - Dec 2022


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