Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children MIS-C, 2024, Bellos et al.

[SNT Gatchaman]

Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children MIS-C
Bellos, Evangelos and 97 others

Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, “burdenMC,” which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5–5.3, P < 10−6).

BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status.

These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.

Link | PDF | Journal of Experimental Medicine [Open Access]

 

[SNT Gatchaman]

This analysis revealed butyrophilin-like 8 (BTNL8), encoding a protein expressed on healthy intestinal epithelial cells modulating intestinal Vγ4+γδ T cells, to be significantly enriched for rare predicted-deleterious variants at an exome-wide significance level (P < 10−6 ). A total allele count of 20 representing 8 variants including 1 pLOF variant was identified across 12 patients, accounting for 8.3% of our cohort. BTNL8 was the only gene exhibiting a strong signal across multiple ancestries. A further 12 genes were significantly burdened in the combined analysis, with support from only a single ancestral group. […] Notably, two of the largest ancestral groups in our MIS-C cohort (EUR and AMR) exhibit a standalone statistically significant burden, while the other two (AFR and SAS) are nominally significant.

BTNL8 is very evidently expressed exclusively by intestinal epithelial cells and also reportedly by neutrophils. BTNL3 is predominantly expressed in intestinal tissues and exhibits very low (arguably negligible) expression in blood.

BTNL8 was found to be specifically associated with MIS-C and not COVID-19 or invasive bacterial diseases, contributing a fourfold increased odds of presenting with MIS-C symptoms. Notably, the BTNL8 burden signal is driven largely by the European and Hispanic sub-cohorts, suggesting that the excess risk of BTNL8-related MIS-C is borne disproportionately by individuals of those ancestries.

We tested all 25 rare BTNL8 variants from both MIS-C cohorts and found 8 to be functionally impaired accounting for 18 MIS-C patients affecting 2.3% of all MIS-C patients (n = 835). Notably, 6 of 8 functionally impaired variants were located within the B30.2 domain, which in other contexts has been shown to mediate protein-protein interactions and/or sensing of intracellular metabolites.

The other reported site of BTNL8 expression is the human gut epithelium where its co-expression with BTNL3 critically regulates intraepithelial Vγ4+ T cells that are implicated in maintaining and/or restoring the integrity of the gut barrier. Indeed, a common hypomorphic variant allele fusing BTNL8 and BTNL3 is associated with disease-modifying exacerbation of Crohn’s disease, consequent to dysregulation of gut Vγ4+ cells

the prospect that the reduction in the surface expression and/or function of BTNL8 may result in hyperinflammation of the gut and increased intestinal permeability is completely consistent with increased gut permeability documented in most of our MIS-C patients, and invariably in those with variant BTNL8 alleles.