Exome sequencing and pathway analysis for identification of genetic variability relevant for bronchopulmonary dysplasia (BPD) in preterm newborns: A pilot study

Clin Chim Acta. 2015 Dec 7;451(Pt A):39-45. doi: 10.1016/j.cca.2015.01.001. Epub 2015 Jan 8.


Background: Bronchopulmonary dysplasia (BPD) is the most common chronic lung disease in infancy, affecting preterm children with low birth weight. The disease has a multifactorial aetiology with a significant genetic component; until now published association studies have identified several candidate genes but only few of these data has been replicated. In this pilot study, we approached exome sequencing aimed at identifying non-common variants, which are expected to have a stronger phenotypic effect.

Materials and methods: We performed this study on 26 Italian severely affected BPD preterm unrelated newborns, homogeneously selected from a large prospective cohort. We used an Illumina HiSeq 2000 for sequencing. Data analysis was focussed on genes previously associated to BPD susceptibility and to new candidates in related pathways, highlighted by a prioritization analysis performed using ToppGene Suite.

Results: By exome sequencing, we identified 3369 novel variants, with a median of 400 variations per sample. The top candidate genes highlighted were NOS2, MMP1, CRP, LBP and the toll-like receptor (TLR) family. All of them have been confirmed with Sanger sequencing.

Conclusions: Potential candidate genes have been discovered in this preliminary study; the pathogenic role of identified variants will need to be confirmed with functional and segregation studies and possibly with further methods, able to evaluate the collective influence of rare variants. Moreover, additional candidates will be tested and genetic analysis will be extended to all affected children.

Keywords: Bronchopulmonary dysplasia; Exome sequencing; Genetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Bronchopulmonary Dysplasia / diagnosis
  • Bronchopulmonary Dysplasia / genetics*
  • DNA / genetics
  • Exome / genetics*
  • Genetic Variation / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Infant, Premature / blood
  • Infant, Premature / metabolism*
  • Intensive Care Units, Neonatal
  • Pilot Projects


  • DNA