Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C) - 03/09/21

Doi : 10.1016/j.jaci.2021.06.024

Janet Chou, MD ^a,^⁎^{∗
These authors contributed equally to this work.} , Craig D. Platt, MD, PhD ^a,^{∗
These authors contributed equally to this work.}, Saddiq Habiballah, MD ^a, Alan A. Nguyen, MD ^a, Megan Elkins, MHS ^a, Sabrina Weeks, BA ^a, Zachary Peters, BA ^a, Megan Day-Lewis, RN, MSN, CPNP ^a, Tanya Novak, PhD ^b, Myriam Armant, PhD ^c, Lucinda Williams, RN, PNP, DNP, NE-BC ^d, Shira Rockowitz, PhD ^e,^f, Piotr Sliz, PhD ^e,^f, David A. Williams, MD ^g,^h,ⁱ, Adrienne G. Randolph, MD, MSc ^b,^{^{‡
These authors contributed equally to this work.}}, Raif S. Geha, MD ^a,^{^{‡
These authors contributed equally to this work.}}
for the
Taking on COVID-19 Together Study Investigators^{^§}
The Taking on COVID-19 Together Investigators are as follows: Abduarahman Almutairi, MD, Faris Jaber, MD, Tina Banzon, MD, Jordan Roberts, MD, Olha Halyabar, MD, Mindy Lo, MD, PhD, Stacy Kahn, MD, Lauren A. Henderson, MD, MMSc, Pui Y. Lee, MD, PhD, Mary Beth Son, MD, and Leah Cheng, MMSc.
Abduarahman Almutairi, MD, Faris Jaber, MD, Tina Banzon, MD, Jordan Roberts, MD, Olha Halyabar, MD, Mindy Lo, MD, PhD, Stacy Kahn, MD, Lauren A. Henderson, MD, MMSc, Pui Y. Lee, MD, PhD, Mary Beth Son, MD, Leah Cheng, MMSc

^a Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^b Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^c The TransLab, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^d The Institutional Centers for Clinical and Translational Research, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^e Computational Health Informatics Program, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^f The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^g Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston, Mass
^h Department of Pediatric Oncology, the Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass
ⁱ Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston Children’s Hospital, Harvard Medical School, Boston, Mass

^∗Corresponding author: Janet Chou, MD, One Blackfan Circle, Karp Bldg, 10th Floor, Boston, MA 02115.One Blackfan CircleKarp Bldg10th FloorBostonMA02115

Abstract

Background

Multisystem inflammatory syndrome in children (MIS-C) is a pediatric complication of severe acute respiratory syndrome coronavirus 2 infection that is characterized by multiorgan inflammation and frequently by cardiovascular dysfunction. It occurs predominantly in otherwise healthy children. We previously reported haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of type I and II interferons, as a genetic risk factor for MIS-C.

Objectives

We aimed to identify additional genetic mechanisms underlying susceptibility to severe acute respiratory syndrome coronavirus 2–associated MIS-C.

Methods

In a single-center, prospective cohort study, whole exome sequencing was performed on patients with MIS-C. The impact of candidate variants was tested by using patients’ PBMCs obtained at least 7 months after recovery.

Results

We enrolled 18 patients with MIS-C (median age = 8 years; interquartile range = 5-12.25 years), of whom 89% had no conditions other than obesity. In 2 boys with no significant infection history, we identified and validated hemizygous deleterious defects in XIAP, encoding X-linked inhibitor of apoptosis, and CYBB, encoding cytochrome b-245, beta subunit. Including the previously reported SOCS1 haploinsufficiency, a genetic diagnosis was identified in 3 of 18 patients (17%). In contrast to patients with mild COVID-19, patients with defects in SOCS1, XIAP, or CYBB exhibit an inflammatory immune cell transcriptome with enrichment of differentially expressed genes in pathways downstream of IL-18, oncostatin M, and nuclear factor κB, even after recovery.

Conclusions

Although inflammatory disorders are rare in the general population, our cohort of patients with MIS-C was enriched for monogenic susceptibility to inflammation. Our results support the use of next-generation sequencing in previously healthy children who develop MIS-C.

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Graphical abstract

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Key words : Multisystem inflammatory syndrome in children, MIS-C, COVID-19, SARS-CoV-2, whole exome sequencing

Abbreviations used : CGD, COVID-19, CYBB, HLH, IVIG, MIS-C, NOD2, SARS-CoV-2, SOCS1, TLR, WES, XIAP

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Introduction

Results and discussion

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Supported by the National Institute of Allergy and Infectious Diseases (grants R01-AI139633 [to R.S.G.], R01-AI139633-S1 [to R.S.G., J.C., and A.G.R.], R01-AI154470 [to A.G.R.], the Centers for Disease Control and Prevention (grant 75D30120C07725 [to A.G.R. and J.C.]), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant R21-HD095228 [to A.G.R.]), the Perkin Fund (to R.S.G.), and the Samara Jan Turkel Center for Autoimmune Diseases (to J.C.), as well as by the Institutional Centers for Clinical and Translational Research and the Children’s Rare Disease Cohorts initiative at Boston Children’s Hospital.

Esportazione

Vol 148 - N° 3

P. 732 - Settembre 2021 Ritorno al numero

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Mechanisms underlying genetic susceptibility to multisystem inflammatory syndrome in children (MIS-C) - 03/09/21

Abstract

Background

Objectives

Methods

Results

Conclusions

Graphical abstract

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