AUTHOR=Asgari Samira , McLaren Paul J. , Peake Jane , Wong Melanie , Wong Richard , Bartha Istvan , Francis Joshua R. , Abarca Katia , Gelderman Kyra A. , Agyeman Philipp , Aebi Christoph , Berger Christoph , Fellay Jacques , Schlapbach Luregn J. ,  The Swiss Pediatric Sepsis Study , Posfay-Barbe Klara , Giannoni Eric , Aebi Christoph , Agyeman Philipp , Wagner Bendicht P. , Schlapbach Luregn J. , Heininger Ulrich , Konetzny Gabriel , Donas Alex , Stocker Martin , Leone Antonio , Hasters Paul , Niederer-Loher Anita , Kahlert Christian , Baer Walter , Relly Christa , Berger Christoph 

TITLE=Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis

JOURNAL=Frontiers in Immunology

VOLUME=7

YEAR=2016

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2016.00357

DOI=10.3389/fimmu.2016.00357

ISSN=1664-3224

ABSTRACT=<p>One out of three pediatric sepsis deaths in high income countries occur in previously healthy children. Primary immunodeficiencies (PIDs) have been postulated to underlie fulminant sepsis, but this concept remains to be confirmed in clinical practice. <italic>Pseudomonas aeruginosa</italic> (<italic>P. aeruginosa</italic>) is a common bacterium mostly associated with health care-related infections in immunocompromised individuals. However, in rare cases, it can cause sepsis in previously healthy children. We used exome sequencing and bioinformatic analysis to systematically search for genetic factors underpinning severe <italic>P. aeruginosa</italic> infection in the pediatric population. We collected blood samples from 11 previously healthy children, with no family history of immunodeficiency, who presented with severe sepsis due to community-acquired <italic>P. aeruginosa</italic> bacteremia. Genomic DNA was extracted from blood or tissue samples obtained intravitam or postmortem. We obtained high-coverage exome sequencing data and searched for rare loss-of-function variants. After rigorous filtrations, 12 potentially causal variants were identified. Two out of eight (25%) fatal cases were found to carry novel pathogenic variants in PID genes, including <italic>BTK</italic> and <italic>DNMT3B</italic>. This study demonstrates that exome sequencing allows to identify rare, deleterious human genetic variants responsible for fulminant sepsis in apparently healthy children. Diagnosing PIDs in such patients is of high relevance to survivors and affected families. We propose that unusually severe and fatal sepsis cases in previously healthy children should be considered for exome/genome sequencing to search for underlying PIDs.</p>