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Exome sequencing of extreme phenotypes in bronchopulmonary dysplasia

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Abstract

Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants with growing evidence that genetic factors contribute largely to moderate and severe cases. We assessed by exome sequencing if rare genetic variants could account for extremely severe phenotypes. We selected 6 infants born very preterm with severe bronchopulmonary dysplasia and 8 very preterm born controls for exome sequencing. We filtered whole exome sequencing results to include only rare variants and selected variants and/or genes with variants that were present in at least 2 cases and absent in controls. We selected variants, all heterozygous, in 9 candidate genes, 7 with a putative role in lung development and 2 that displayed 3 variations in 3 different cases, independently of their potential role in lung development. Sequencing of 5 other severe cases for these variants did not replicate our results.

Conclusion: In selected preterm born infants with severe bronchopulmonary dysplasia and controls, we failed to find any rare variant shared by several infants with an extremely severe phenotype. Our results are not consistent with the role of rare causative variants in bronchopulmonary dysplasia’s development and argue for the highly polygenic nature of susceptibility of this disorder.

What is Known:

• Bronchopulmonary dysplasia is a multifactorial disease resulting from complex environmental and genetic interactions occurring in an immature lung.

• It is not known whether rare genetic variants in coding regions could account for extreme phenotypes of the disease.

What is New:

• In a group of infants with an extreme phenotype of bronchopulmonary dysplasia and in comparison to controls, no common genetic variants were found, nor did variants that were select in other exome studies in this setting.

• These results argue for the highly polygenic nature of susceptibility of bronchopulmonary dysplasia.

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Abbreviations

ACTN4:

Actinin alpha 4

ADAMTS17:

ADAM metallopeptidase with thrombospondin type 1 motif 17

BPD:

Bronchopulmonary dysplasia

CNST:

Consortin, connexin sorting protein

DNA:

Deoxyribonucleic acid

GWAS:

Genome-wide association study

HDAC10:

Histone deacetylase 10

KIF16B:

Kinesin family member 16B

NUMA1:

Nuclear mitotic apparatus protein 1

SCUBE3:

Signal peptide, CUB domain and EGF like domain containing 3

SIFT:

Sorting intolerant from tolerant

SNP:

Single nucleotide polymorphism

SPOCK2:

SPARC/osteonectin, CWCV, and Kazal-like domains proteoglycan 2

UV:

Ultra-violet

wPMA:

Weeks of post-menstrual age

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Funding

We thank Houria Abbas, Patrick Ledudal, and Dr. Jérôme Barré from the Centre de Ressources Biologiques of the Centre Hospitalier Intercommunal de Créteil for the DNA extraction and samples conservation. This study and AH were funded by l’Agence Nationale de la Recherche (ANR-12-BSV1-0004-01). AH was also funded by la Fondation du Souffle et le Fonds de Recherche en Santé Respiratoire.

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Authors and Affiliations

  1. AP-HP, Hôpital Necker-Enfants Malades, Service de Pneumologie Pédiatrique, Centre de Référence pour les Maladies Respiratoires Rares de l’Enfant, Paris, France

    Alice Hadchouel & Christophe Delacourt

  2. INSERM U1151, Institut Necker Enfants Malades, Paris, France

    Alice Hadchouel & Christophe Delacourt

  3. Faculté de médecine, Université de Paris, Paris, France

    Alice Hadchouel & Christophe Delacourt

  4. Service De Réanimation Néonatale, Centre Hospitalier Intercommunal, Créteil, France

    Fabrice Decobert

  5. Inserm UMR1163, Imagine Institute, Translational Genetics Laboratory, 24 Boulevard du Montparnasse, 75015, Paris, France

    Claude Besmond

Authors
  1. Alice Hadchouel
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  2. Fabrice Decobert
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  3. Claude Besmond
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  4. Christophe Delacourt
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Contributions

Drs. Hadchouel, Besmond, and Pr Delacourt conceptualized and designed the study. Drs. Hadchouel, Decobert, and Pr Delacourt contributed to acquisition and interpretation of data. Dr. Hadchouel and Pr Delacourt drafted the initial manuscript. Drs Hadchouel, Decobert, Besmond, and Pr Delacourt reviewed and revised the manuscript, and all authors approved the final manuscript as submitted.

Corresponding author

Correspondence to Alice Hadchouel.

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Signed written informed consent was obtained from the parents and the study was approved by the local ethics committee (CPP Île-de-France IX).

Conflict of interest

The authors declare that they have no conflict of interest.

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Communicated by Peter de Winter

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Hadchouel, A., Decobert, F., Besmond, C. et al. Exome sequencing of extreme phenotypes in bronchopulmonary dysplasia. Eur J Pediatr 179, 579–586 (2020). https://doi.org/10.1007/s00431-019-03535-0

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  • DOI: https://doi.org/10.1007/s00431-019-03535-0

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