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Exome sequencing and pathway analysis for identification of genetic variability relevant for bronchopulmonary
Paola Carrera1, Chiara Di Resta2, Chiara Volonteri3
1Unit of Genomics for Diagnosis of Human Pathologies, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milano, Italy; Laboratory of Clinical Molecular Biology, IRCCS Ospedale San Raffaele, Milano, Italy.
Insights
This study identified novel genetic variants in infants with bronchopulmonary dysplasia (BPD), a common lung disease in premature infants. Further research will confirm the role of these candidate genes in BPD development.
Area of Science:
- Genetics
- Neonatology
- Pulmonology
Background:
- Bronchopulmonary dysplasia (BPD) is a prevalent chronic lung disease in premature infants.
- It has a multifactorial etiology with a significant genetic component.
- Previous genetic association studies have yielded few replicated findings.
Purpose of the Study:
- To identify novel genetic variants associated with severe BPD in preterm infants.
- To explore the role of rare genetic variants in BPD pathogenesis.
- To investigate candidate genes potentially influencing BPD susceptibility.
Main Methods:
- Exome sequencing was performed on 26 Italian preterm infants with severe BPD.
- Data analysis focused on previously associated BPD genes and prioritized new candidates using ToppGene Suite.
- Identified variants were confirmed using Sanger sequencing.
Main Results:
- Exome sequencing identified 3369 novel variants, averaging 400 per sample.
- Top candidate genes included NOS2, MMP1, CRP, LBP, and the toll-like receptor (TLR) family.
- All highlighted candidate genes were validated via Sanger sequencing.
Conclusions:
- This pilot study discovered potential candidate genes for BPD.
- Functional and segregation studies are needed to confirm the pathogenic role of identified variants.
- Further research will explore rare variant influence and expand genetic analysis to more affected infants.
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.
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