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

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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.

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External Organisations
Liverpool Hospital; Children's Hospital at Westmead; University of New South Wales (UNSW); Sydney Children's Hospitals Network; Murdoch Children's Research Institute; Prince of Wales Hospital; Monash Children's Hospital; Royal Children's Hospital; Queensland Children's Hospital; Canberra Hospital

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