Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C)

Area of Science:

• Immunology
• Genetics
• Gastroenterology

Background:

• Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition following SARS-CoV-2 infection.
• Intestinal manifestations are common in MIS-C, suggesting a role for gut health.
• Genetic factors, including inborn errors of the OAS-RNAseL pathway, have been implicated in MIS-C susceptibility.

Purpose of the Study:

• To investigate the genetic basis of MIS-C, focusing on potential links to intestinal manifestations.
• To identify specific genes and variants associated with MIS-C risk using a novel gene burden analysis framework.
• To explore the functional consequences of identified genetic variants on gut homeostasis and immune cell function.

Main Methods:

• Sequencing of 154 MIS-C patients to identify genetic variants.
• Application of a novel statistical framework, "burdenMC," for gene burden analysis.
• Functional testing of BTNL8 variants in a larger cohort (n=835) using an assay for Vγ4+γδ T cell engagement.
• Assessment of intestinal permeability in relation to identified variants.

Main Results:

• Enrichment of rare, predicted-deleterious variants in the BTNL8 gene was found exclusively in MIS-C patients (OR = 4.2, P < 10-6).
• BTNL8 encodes a regulator of Vγ4+γδ T cells involved in gut homeostasis.
• Functional tests revealed eight BTNL8 variants in 18 MIS-C patients (2.2%) causing impaired Vγ4+γδ T cell engagement, particularly affecting the B30.2 domain.
• These variants were associated with altered intestinal permeability.

Conclusions:

• Rare variants in BTNL8 are significantly associated with MIS-C, suggesting a genetic predisposition.
• Disrupted BTNL8 function and subsequent impairment of Vγ4+γδ T cell engagement may contribute to MIS-C-associated enteropathy.
• These findings highlight a potential link between gut homeostasis, genetic factors, and SARS-CoV-2-triggered MIS-C.