Monoallelic expression can govern penetrance of inborn errors of immunity

• Published in: Nature (London) Vol. 637; no. 8048; pp. 1186 - 1197
• Main Authors: Stewart, O’Jay, Gruber, Conor, Randolph, Haley E., Patel, Roosheel, Ramba, Meredith, Calzoni, Enrica, Huang, Lei Haley, Levy, Jay, Buta, Sofija, Lee, Angelica, Sazeides, Christos, Prue, Zoe, Hoytema van Konijnenburg, David P., Chinn, Ivan K., Pedroza, Luis A., Lupski, James R., Schmitt, Erica G., Cooper, Megan A., Puel, Anne, Peng, Xiao, Boisson-Dupuis, Stéphanie, Bustamante, Jacinta, Okada, Satoshi, Martin-Fernandez, Marta, Orange, Jordan S., Casanova, Jean-Laurent, Milner, Joshua D., Bogunovic, Dusan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.01.2025; Nature Publishing Group
• Subjects: 13/106; 13/31; 38; 45; 45/23; 45/91; 631/208/199; 631/250/249/2512; Adult; Alleles; Allergies; Autoimmunity; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Clone Cells; Cloning; Disorders; DNA Methylation; Epigenetics; Errors; Female; Gene expression; Gene Expression Regulation - genetics; Genes; Genetic disorders; Genetic variability; Genotype & phenotype; Genotypes; Heterozygote; Histones - metabolism; Humanities and Social Sciences; Humans; Immunity; Leukocytes (mononuclear); Life Sciences; Lymphocytes; Lymphocytes T; Male; multidisciplinary; Mutation; Mutation - genetics; Pedigree; Penetrance; Peripheral blood mononuclear cells; Phenotype; Phenotypes; Science; Science (multidisciplinary); STAT1 Transcription Factor - genetics; T-Lymphocytes - immunology; T-Lymphocytes - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-024-08346-4

Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy 1 . Incomplete penetrance is common among IEIs despite their monogenic basis 2 . Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele 3 , 4 , 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 that 4.30% of IEI genes and 5.20% of all genes undergo aRMAE. Perturbing H3K27me3 and DNA methylation alters allele expression commitment, in support of two proposed mechanisms 5 , 6 for the regulation of aRMAE. We tested peripheral blood mononuclear cells from individuals with IEIs with shared genetic lesions but discordant clinical phenotypes for aRMAE. Among two relatives who were heterozygous for a mutation in PLCG2 (delEx19), an antibody deficiency phenotype corresponds to selective mutant allele expression in B cells. By contrast, among relatives who were heterozygous for a mutation in JAK1 (c.2099G>A; p.S700N), the unaffected carrier T cells predominantly expressed the wild-type JAK1 allele, whereas the affected carrier T cells exhibited biallelic expression. Allelic expression bias was also documented in phenotypically discordant family members with mutations in STAT1 and CARD11 . This study highlights the importance of considering both the genotype and the ‘transcriptotype’ in analyses of the penetrance and expressivity of monogenic disorders. Somatically determined preferential allelic expression of select genes that when mutated cause inborn errors of immunity corresponds with disease phenotypes, suggesting that the penetrance and expressivity of monogenic disorders is also dependent on the ‘transcriptotype’.