451 - Pathogenic variants in surfactant genes are more prevalent in infants with BPD but are not associated with severe disease

Poster Number: 451
Publication Number: 451.431

Alison Almgren-Bell, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Dara Torgerson, University of California San Francisco, San Francisco, CA, United States; Aaron Hamvas, Ann & Robert H. Lurie Children's Hospital of Chicago / Northwestern University, Chicago, IL, United States

Background:
Pathogenic variants in pulmonary surfactant genes cause respiratory disease in term newborns and children, though single variants in the ATP binding cassette member A3 (ABCA3) have been associated with respiratory distress syndrome in late preterm infants.

Objective:
To determine if variants in the genes encoding surfactant proteins B and C (SFTPB, SFTPC), ABCA3, or the thyroid transcription factor (NKX2-1) are over-represented in preterm infants with bronchopulmonary dysplasia (BPD), as defined by need for and duration of supplemental oxygen at 36 weeks post-menstrual age (PMA).

Design/Methods:
We analyzed variation derived from exome sequences of 392 infants born at < 29 weeks’ gestation who were in the Prematurity and Respiratory Outcomes Program (PROP) and who did and did not have BPD (n=176 and 216, respectively). We selected rare ( < 1% frequency), protein altering (non-synonymous, splice site, and frameshift) variants, and inferred pathogenicity through either American College of Medical Genetics classification or Combined Annotation Dependent Depletion (CADD) scores >20 for novel or unclassified variants. Lastly, we interrogated clinical data of individuals that carried these variants to determine if there was anything unusual about their clinical course. 

Results:
We identified 67 missense, frameshift or splice site variants, of which 24 were unique to BPD-affected preterm infants and 20 were unique to unaffected infants. We identified 9 variants that met our criteria for pathogenicity in 12 individuals, none in NKX2-1 and with no individual carrying more than one pathogenic variant. Affected infants were more likely to carry a rare protein altering pathogenic variant in a surfactant gene as compared to unaffected infants (5.1% vs 1.4% respectively, p=0.04, Table 1).  Clinical characteristics of infants with and without pathogenic variants in the affected and unaffected groups were similar, with no differences identified in gestational age, duration of invasive ventilatory support or respiratory support altogether, age of discharge, race or sex distribution (Table 2). Individually, the one infant with SFTPC p.L181V was born at 28 weeks, required invasive respiratory support for 2 weeks and was discharged with supplemental oxygen at 39 weeks PMA. There were no deaths among the individuals with pathogenic variants.
Conclusion(s):
Rare pathogenic protein altering variants in surfactant genes are slightly more prevalent in premature infants with BPD, but we did not identify any distinguishing clinical features of premature infants that carry these pathogenic variants.

Table 1. Pathogenic variants and frequencies
Table 2. Clinical Characteristics