Morgane Gélin (France)
Nantes University Hospital PaediatricsAuthor Of 1 Presentation
IDENTIFICATION OF RARE CAUSAL GENETIC VARIANTS IN INVASIVE PNEUMOCOCCAL DISEASES BY EXOME ANALYSIS IN CHILDREN
Abstract
Backgrounds:
Invasive pneumococcal diseases (IPDs) are severe diseases in children. Host genetic factors are implicated in susceptibility and severity of IPDs. Further understanding of the molecular factors involved in the development of these severe infections could lead to better treatment, prevention, and thus better outcome. Previous studies identified several candidate genes for IPDs, however, mostly because of methodological shortcomings, these results are yet to be confirmed. Our study aimed to identify rare coding genetic variants implicated in the development of IPDs using whole-exome sequencing of 32 children admitted in pediatric intensive care unit for IPD.
Methods
Contrary to most previous studies related to IPDs, we chose an untargeted approach to find novel variants. We developed a bioinformatic analysis pipeline to identify rare, non-synonymous and possibly pathogenic variants implicated in IPDs. Furthermore, we compared the number of variants observed in our 32 patients to an unrelated control population (n=69) to validate our pipeline and discoveries.
Results:
We identified 86 rare variants at heterozygous state in 18 different genes. The control population presented significantly fewer variants (p=7.6x10-16) in fewer genes (p=5.5x10-16). We could, with variants from 6 of these 18 genes, build a highly predictive model perfectly separating cases and controls.
Conclusions/Learning Points:
Our results revealed multiple heterozygous variants in a restricted set of genes for each patient presenting an extreme phenotype of pneumococcal disease, emphasizing the likely polygenicity of IPD risk. In conclusion, these first results suggest an unprecedented immune deficiency involving the association of several rare mutations in immune-related genes. These results may be used to predict the individual risk of children to present IPDs. We will pursue our efforts in characterizing this risk by reproducing our findings with other populations of children with IPDs.
Presenter of 1 Presentation
IDENTIFICATION OF RARE CAUSAL GENETIC VARIANTS IN INVASIVE PNEUMOCOCCAL DISEASES BY EXOME ANALYSIS IN CHILDREN
Abstract
Backgrounds:
Invasive pneumococcal diseases (IPDs) are severe diseases in children. Host genetic factors are implicated in susceptibility and severity of IPDs. Further understanding of the molecular factors involved in the development of these severe infections could lead to better treatment, prevention, and thus better outcome. Previous studies identified several candidate genes for IPDs, however, mostly because of methodological shortcomings, these results are yet to be confirmed. Our study aimed to identify rare coding genetic variants implicated in the development of IPDs using whole-exome sequencing of 32 children admitted in pediatric intensive care unit for IPD.
Methods
Contrary to most previous studies related to IPDs, we chose an untargeted approach to find novel variants. We developed a bioinformatic analysis pipeline to identify rare, non-synonymous and possibly pathogenic variants implicated in IPDs. Furthermore, we compared the number of variants observed in our 32 patients to an unrelated control population (n=69) to validate our pipeline and discoveries.
Results:
We identified 86 rare variants at heterozygous state in 18 different genes. The control population presented significantly fewer variants (p=7.6x10-16) in fewer genes (p=5.5x10-16). We could, with variants from 6 of these 18 genes, build a highly predictive model perfectly separating cases and controls.
Conclusions/Learning Points:
Our results revealed multiple heterozygous variants in a restricted set of genes for each patient presenting an extreme phenotype of pneumococcal disease, emphasizing the likely polygenicity of IPD risk. In conclusion, these first results suggest an unprecedented immune deficiency involving the association of several rare mutations in immune-related genes. These results may be used to predict the individual risk of children to present IPDs. We will pursue our efforts in characterizing this risk by reproducing our findings with other populations of children with IPDs.