Epidemiology of Surfactant Protein-B Deficiency

BACKGROUND:

Respiratory distress syndrome is the most frequent respiratory cause of death and morbidity
in infants less than 1 year of age in the United States. Of approximately 28,500 infant
deaths in 2006, 5,421 (19.7%) were diagnosed with respiratory distress as either the primary
(1,011 - 3.7%) or secondary (4,410 - 16%) cause of death. Despite improvement in infant
mortality rates over the last 20 years, survivors of respiratory distress syndrome with
chronic respiratory disease consume twenty times more annualized dollars than unaffected
children and 5.9% of all dollars spent on children from 0-18 years of age. More recent
estimates including data from California and New York, the Institute of Medicine, and the
2001 Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project suggest
that the average cost of hospitalization for each of the 49,900 infants with a diagnosis of
respiratory distress syndrome was $56,800 vs. $10,700 for a premature infant without
respiratory distress syndrome. The recent increase in late preterm births has contributed to
both the frequency of respiratory distress syndrome and its economic impact. These medical
costs do not include the economic consequences of infant respiratory morbidity for families,
e.g., absence from work, and early intervention costs to optimize outcome. In addition,
despite 2-3 fold greater risk of infant mortality for African American infants than European
American infants from all other causes, European American infants have greater risk of death
from respiratory distress than African American infants, and this increased risk is not
attributable to differences in surfactant phospholipid composition, birth weight, gestational
age, or confounding socioeconomic factors. Understanding the genetic mechanisms that cause
respiratory distress syndrome is critical for improving outcomes of children in the United
States, reducing costs of their health care, and reducing racial disparity in infant
mortality. Since the original description of deficiency of the pulmonary surfactant in
premature newborn infants by Avery and Mead in 1959, respiratory distress syndrome has most
commonly been attributed to developmental immaturity of pulmonary surfactant production.
Despite improvement in neonatal survival associated with availability of surfactant
replacement therapy for premature infants, gender and race based disparities in disease
frequency, morbidity and mortality have persisted, an observation that suggests that genetic
factors play an important role in disease pathogenesis. In addition, twin studies indicate
high heritability (h2) of neonatal respiratory distress syndrome (0.2 and 0.8). Recent
clinical reports of monogenic causes of neonatal respiratory distress syndrome, statistical
association of candidate gene variants with increased disease risk, and studies of targeted
gene ablation in murine lineages have also strongly suggested that genetic mechanisms
contribute to risk of respiratory distress syndrome in newborn infants. When we examined
genetic variants in large population-based and case-control cohorts, we found that the
population-based frequencies of individual, disruptive mutations in 3 candidate genes (SFTPB,
SFTPC, and ABCA3) (<2%) account for <0.1% of the population attributable risk in term or near
term infants, and that individual, rare, disruptive mutations are not associated with disease
in case-control cohorts. In addition, when we attempted to establish an association between
an intermediate biochemical phenotype (surfactant protein-B peptide mobility on western blot)
and SFTPB variants (assessed by complete resequencing) in term and near term infants with and
without respiratory distress, we failed to identify a SFTPB variant or combination of
variants associated with respiratory distress and altered surfactant protein-B structure.
Finally, we have recently found that tagSNPs in genes from gene networks expressed in lung
but not part of the pulmonary surfactant network (ion channel, lung remodeling, and unfolded
protein response genes) confer race-specific risk of neonatal respiratory distress syndrome.
These studies suggest that variation in SFTPB, SFTPC, and ABCA3 is under significant
purifying selection pressure and that the genetic contribution to neonatal respiratory
distress syndrome is based on contributions of rare, independent risk alleles in multiple
genes and gene networks.

DESIGN NARRATIVE:

Rare mutations in the surfactant protein-B gene (SFTPB) and other genes in the pulmonary
surfactant metabolic network cause lethal neonatal respiratory distress syndrome in human
newborn infants by disrupting metabolism and function of the pulmonary surfactant. Mutation
frequencies (<1-2%) in SFTPB and 2 other candidate genes in the pulmonary surfactant network
(SFTPC and ABCA3) do not account for heritability of neonatal respiratory distress syndrome
(h2~0.2-0.8) suggested by twin studies. To develop a comprehensive catalogue of genes and
gene networks that account for the heritability of this complex disease, we propose to test
the hypothesis that excess, rare, functionally disruptive single nucleotide polymorphisms
(SNPs) characterize genes and gene networks associated with increased risk of neonatal
respiratory distress syndrome. Specifically, using trio whole exome or whole genome
sequencing of affected infant (progressive, severe respiratory distress in term or near term
infants or children with unexplained interstitial lung disease or other rare lung
phenotypes)/parent trios, we will identify de novo or recessively inherited pathogenic
variants including single nucleotide variants, small insertions/deletions, and copy number or
structural variants (>100 kb). To predict pathogenicity, we will use a suite of computational
prediction algorithms (e.g., ANNOVAR, CADD). To confirm variants in genes and gene pathways
not previously associated with human infant/child rare respiratory phenotypes, we will use
GeneMatcher to identify other affected infants with pathogenic variants at the same gene
locus or in the same gene pathway or functional testing of identified variants in a variety
of cell-based jor model organism models. Using next-generation sequencing technology and
state of the art statistical methods to elucidate the genetic complexity of neonatal
respiratory distress syndrome and rare infant lung phenotypes will permit the development of
personalized diagnostic tools and preventive therapeutic strategies for high risk infants and
young children.

Inclusion Criteria:

- Normal pulmonary function or a diagnosis of RDS

Exclusion Criteria: