365 - Pathogenic variants in surfactant genes are not associated with negative clinical outcomes in infants with BPD

Publication Number: 1349.365

Jumobi I. Arowolo, Northwestern University The Feinberg School of Medicine, Bolingbrook, IL, United States; Alison Almgren-Bell, Northwestern University The Feinberg School of Medicine, Chicago, IL, United States; Thaybeth I.. Malavé-Méndez, University of California, San Francisco, School of Medicine, San Francisco, CA, United States; Dara G. Torgerson, University of California, San Francisco, San Francisco, CA, United States; Aaron Hamvas, Lurie Children's Hospital / Northwestern University, Chicago, IL, United States

Background: Diffuse lung diseases (DLD) in children are often caused by pathogenic genetic variants. Bronchopulmonary dysplasia (BPD), the most common chronic respiratory disease of prematurity, is of varying severity in its clinical course.

Objective: To determine if genetic variants in DLD-associated genes are over-represented in infants with BPD.

Design/Methods: In exome data from 380 infants born < 29 weeks’ gestation (BPD=170, NO-BPD=210) from the Prematurity and Respiratory Outcomes Program (PROP), we investigated 9 genes for presence of a potentially pathogenic variant. Pathogenic variants were defined as rare ( < 5% frequency), protein altering (non-synonymous, splice site, and frameshift) variants, and Combined Annotation Dependent Depletion (CADD) scores >20, or inferred pathogenicity through the American College of Medical Genetics classification. Infants who required any respiratory support and demonstrated a need for supplemental oxygen at 36 weeks PMA were classified as BPD. All infants in the study survived until discharge. We interrogated clinical data of individuals that carried these variants to determine if there was a correlation between variant presence and severity of clinical course.

Results: We identified 41 pathogenic variants across 8 genes in 54 individuals. Two infants in the NO-BPD group had one variant in two different genes; all other infants had one variant. Variants were present in 15% of BPD and 14% of NO-BPD; 52% of those with a variant had BPD and 48% without a variant had BPD (P=0.61). There was no difference in the post-menstrual age at which liberation from invasive ventilation (33.8 ± 6.0 vs 33.5 ± 6.1 weeks, VAR-POS vs VAR-NEG respectively) or supplemental oxygen (41.4 ± 4.2 vs 41.1 ± 4.4 weeks, VAR-POS vs VAR-NEG respectively) occurred. Of infants born at 27-28 weeks with BPD, 17% had a variant compared with 12% NO-BPD (P=0.27). Based on questionnaire data assessing hospitalization for respiratory indications, home respiratory support, respiratory medications, or respiratory symptoms, 72% of the infants with a variant had persistent respiratory disease compared with 61% without a variant (P=0.12).

Conclusion(s): Pathogenic variants were present in this premature population at the frequency anticipated based on population-based data. There was no difference in respiratory severity in the infants with and without variants. In the absence of identifiable clinical characteristics that distinguish those with and without variants, routine genetic testing in infants with BPD is not likely to yield actionable information.