Covid-19: genetic defects responsible for multisystemic inflammatory syndrome in children

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Electron microscopy of a cell infected with SARS-CoV-2 © Philippe Roingeard, Ann
Electron microscopy of a cell infected with SARS-CoV-2 © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, Inserm Unit U1259 MAVIVH & University of Tours, France
The team from the Human Genetics of Infectious Diseases Laboratory of the Necker-Enfants malades AP-HP Hospital, Inserm, Université Paris Cité within the Imagine Institute, leading the international consortium COVID Human Genetic Effort ( ) coordinated by Prof. Jean-Laurent Casanova and Prof. Laurent Abel, has discovered genetic defects responsible for multi-systemic inflammatory syndrome in children (MIS-C), following infection with SARS-CoV-2. The results of this study were published on December 20, 2022 in the journal Science.

Multisystemic inflammatory syndrome of children is a new systemic inflammatory entity in children that has emerged in the epidemic context of SARS-Cov-2 infection. It is a rare and severe condition that strongly resembles Kawasaki disease. This syndrome is misunderstood and the suggestive symptoms (fever, altered general condition and digestive disorders) are not very specific, which may lead to a delay in diagnosis, especially since SARS-CoV-2 infection is often not very symptomatic, or even asymptomatic, in children.

It is estimated to affect approximately 1 in 10,000 children infected with SARS-CoV-2. This syndrome usually occurs four weeks after infection.

The objective of this study was to identify a cause of MIS-C following SARS-CoV-2 infection.

558 patients with MIS-C, aged three months to 19 years, from 16 different countries (60.4% boys and 39.6% girls) were analyzed. The study focused on five of these patients aged between three months and 14 years because of their specific genetic characteristics. Indeed, these patients had mutations responsible for a loss of function in a zone of their genome (affecting the OAS1, OAS2 and RNASEL genes). As these mutations were recessive, the children had to have two copies inherited from each of their parents for them to be expressed. This specificity suggested that these genetic mutations were probably responsible for the development of MIS-C.

They were compared immunologically to healthy children and to children with SARS-CoV-2 infection. In children with a mutation in the OAS-RNase L pathway, an excess response to the virus was observed in certain immune cells: phagocytes.

It is now known that the body’s response to SARS-Cov2 must be finely regulated in order to defend itself properly. Under-activation of the immune system prevents the body from fighting SARS-CoV-2 properly, but conversely, over-activation of the immune system can also lead to serious dysfunctions.

The study therefore identified genetic deficiencies that explain MIS-C. These deficiencies excessively increase the inflammatory response triggered by SARS-CoV-2 in phagocytic cells (monocytes, dendritic cells etc).

More generally, the data from this work demonstrate that the OAS1, OAS2 and RNASEL pathway is essential for the proper regulation of immunity to SARS-CoV-2, by limiting the inflammation produced by phagocytes in contact with the virus.


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