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Observational Study
. 2025 Apr;60(4):e71073.
doi: 10.1002/ppul.71073.

Genetic Testing Utilization in the U.S. Registry for Childhood Interstitial and Diffuse Lung Diseases

Laura A Voss  1   2 , Rebekah J Nevel  3 , Jennifer A Wambach  4 , Lawrence M Nogee  5 , Robin R Deterding  6 , Alicia M Casey  7 , Michael G O'Connor  8 , Daniel I Craven  9 , Jane B Taylor  10 , Gail H Deutsch  11 , Jade B Tam-Williams  12 , Lea C Steffes  13 , Steven K Brennan  14 , Maria T Santiago  15 , Sara C Sadreameli  16 , Andrea F Heras  17 , Michael R Powers  18 , Antonia P Popova  19 , Manvi Bansal  20 , Aaron Hamvas  21 , William A Gower  22 , Fernando Urrego  23 , Lisa R Young  24 ; ChILD Registry Collaborative
Affiliations
Observational Study

Genetic Testing Utilization in the U.S. Registry for Childhood Interstitial and Diffuse Lung Diseases

Laura A Voss et al. Pediatr Pulmonol. 2025 Apr.

Abstract

Introduction: Childhood interstitial and diffuse lung diseases (chILD) comprise a diverse group of rare disorders. Identifying the underlying cause is crucial for treatment, prognosis, and estimating recurrence risk. The objective of this study was to assess the utilization of genetic testing for subjects enrolled in the United States National Registry for ChILD, a multicenter observational study.

Methods: Genetic data from participating sites were reviewed and analyzed in relationship to clinical characteristics.

Results: Of 609 children enrolled from 22 centers, genetic testing was performed for 55.5% (n = 338). Genetic testing results were positive (diagnostic) for 22.8% (n = 77), negative for 60.7% (n = 205), and uncertain for 16.6% (n = 56). Most testing was performed through gene panels (55.9%), followed by exome sequencing (ES) or whole genome sequencing (WGS) (26.9%), single gene testing (24.6%), and/or chromosomal microarray (11.8%). For participants with positive (diagnostic) genetic testing results, the majority were diagnosed through gene panel (33.8%; n = 26) or single gene testing (32.5%; n = 25). The most common diagnosis confirmed by genetic testing was SFTPC-associated surfactant metabolism dysfunction. Of the 59 subjects with unclassified ILD, only 22% (n = 13) had undergone ES or WGS, 61% (n = 36) had received panel testing, and 27% (n = 16) did not have any genetic testing reported.

Conclusion: The utilization of genetic testing has been variable in infants and children enrolled in the ChILD Registry. Additional efforts are needed to develop genetic testing recommendations for children with suspected ILD. Furthermore, there is opportunity for broader utilization of ES/WGS and genetic discovery for children with lung disease of unclear etiology.

Keywords: childhood interstitial lung disease (chILD); genetic testing; rare lung diseases.

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Conflict of interest statement

L.R.Y.: receives royalties from Wolters Kluwer for authorship in UpToDate, consultant for Boehringer Ingelheim pediatric advisory board (outside the submitted work). J.B.T.‐W.: site investigator for Astra Zeneca (not related to interstitial lung disease). G.H.D.: Pathology consultant for Boehringer Ingelheim InPedILD trial; Pathology consultant for 4DMT. M.R.P – Site Investigator for Vertex Pharmaceuticals (not related to interstitial lung disease). W.A.G.: receives royalties from Wolters Kluwer for authorship in UpToDate. R.R.D.: receives royalties from Elsevier for editorship of Kendig and Wilmott's Disorders of the Respiratory Tract in Children, consultation for Boehringer Ingelheim pediatric advisory board and principal investigator for the INPEDILD and INPEDILD‐ ON trial. All other authors report no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Genetic testing utilization and outcome for U.S. ChILD Registry subjects. Of the 609 subjects, 338 underwent genetic testing. Positive outcome refers to genetic testing that was diagnostic and identified underlying genetic cause for subject's pulmonary symptoms. Uncertain outcome refers to subjects who had genetic testing that identified variants of uncertain significance (VUS) in relevant genes, subjects with limited genetic information, or identification of variants in candidate genes. Negative outcome refers to subjects who had genetic testing, but it did not identify any disease‐causing variants and a possible genetic explanation for subject's pulmonary symptoms. [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 2
FIGURE 2
Genetic testing modalities ordered and diagnostic yield. (A) Total number of genetic tests ordered and the diagnostic outcome by testing modality. Across the 338 subjects that underwent genetic testing, 434 different instances of genetic testing were reported. Total number of individual tests is indicated along the Y axis. (B) Genetic testing modality proportions and diagnostic yield. Targeted refers to single gene sequencing or targeted variant analysis. Other test modalities include karyotypes, telomere testing, and transcriptome analysis. Unknown refers to instances when a specific test modality was not documented in registry form. Abbreviations: ES/WGS, exome sequencing/whole genome sequencing. [Color figure can be viewed at wileyonlinelibrary.com]
FIGURE 3
FIGURE 3
Genetic testing modality ordered by year. Between 2007 and 2023, 373 different genetic tests were ordered for Registry subjects. The chart only includes reported instances of microarrays, targeted testing, gene panels, and ES/WGS. Data shown does not include genetic testing performed before 2007 or tests for which year of test was not documented in the Registry. From 1999 to 2007, a maximum of four genetic tests were reported for any given year. Abbreviations: ES/WGS, exome sequencing/whole genome sequencing. [Color figure can be viewed at wileyonlinelibrary.com]
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