Automal Random Allelic Expression (aRMAE) analysis in clonally expanded T cells from healthy donors

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy, and/or malignancy. Incomplete penetrance is common among IEIs despite their monogenic basis. Herein we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to expression of one allele, to phenotypic variability observed in families with IEIs. Using a clonal primary T cell system to assess aRMAE status of genes in healthy individuals, we find 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, supporting two proposed mechanisms for regulation of aRMAE. We tested PBMCs from individuals sharing genetic lesions but with discordant clinical phenotypes in seven families with different IEIs for aRMAE. Among relatives heterozygous for a mutation in PLCG2, an antibody deficiency phenotype corresponds with selective mutant allele expression in B cells. In contrast, among relatives heterozygous for a mutation in JAK1, the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, while the affected carrier T cells exhibited biallelic expression. Selective expression of a single allele was documented in phenotypically discordant family members carrying an AD Loss-of-function (LoF) mutation in STAT1, CARD11, as well as gain-of-function (GoF) mutations in STAT1. This study highlights the importance of not only considering genotype but also the “transcriptotype” in the analyses of the penetrance and expressivity of monogenic disorders.