Monoallelic expression can govern penetrance of inborn errors of immunity

O’Jay Stewart, Conor Gruber, Haley E. Randolph, Roosheel Patel, Meredith Ramba, Enrica Calzoni, Lei Haley Huang, Jay Levy, Sofija Buta, Angelica Lee, Christos Sazeides, Zoe Prue, David P. Hoytema van Konijnenburg, Ivan K. Chinn, Luis A. Pedroza, James R. Lupski, Erica G. Schmitt, Megan A. Cooper, Anne Puel, Xiao Peng, Stéphanie Boisson-Dupuis, Jacinta Bustamante, Satoshi Okada, Marta Martin-Fernandez, Jordan S. Orange, Jean-Laurent Casanova, Joshua D. Milner and Dusan Bogunovic ()
Additional contact information
O’Jay Stewart: Columbia University
Conor Gruber: Icahn School of Medicine at Mount Sinai
Haley E. Randolph: Columbia University
Roosheel Patel: Icahn School of Medicine at Mount Sinai
Meredith Ramba: Columbia University
Enrica Calzoni: Columbia University
Lei Haley Huang: Columbia University
Jay Levy: Icahn School of Medicine at Mount Sinai
Sofija Buta: Columbia University
Angelica Lee: Columbia University
Christos Sazeides: Columbia University
Zoe Prue: Columbia University
David P. Hoytema van Konijnenburg: Harvard Medical School
Ivan K. Chinn: Baylor College of Medicine
Luis A. Pedroza: Columbia University
James R. Lupski: Baylor College of Medicine
Erica G. Schmitt: Washington University School of Medicine
Megan A. Cooper: Washington University School of Medicine
Anne Puel: INSERM UMR1163
Xiao Peng: Johns Hopkins University School of Medicine
Stéphanie Boisson-Dupuis: INSERM UMR1163
Jacinta Bustamante: INSERM UMR1163
Satoshi Okada: Hiroshima University Graduate School of Biomedical and Health Sciences
Marta Martin-Fernandez: Columbia University
Jordan S. Orange: Columbia University
Jean-Laurent Casanova: INSERM UMR1163
Joshua D. Milner: Columbia University
Dusan Bogunovic: Columbia University

Nature, 2025, vol. 637, issue 8048, 1186-1197

Abstract: Abstract Inborn errors of immunity (IEIs) are genetic disorders that underlie susceptibility to infection, autoimmunity, autoinflammation, allergy and/or malignancy1. Incomplete penetrance is common among IEIs despite their monogenic basis2. Here we investigate the contribution of autosomal random monoallelic expression (aRMAE), a somatic commitment to the expression of one allele3,4, 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 mechanisms5,6 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.

Date: 2025
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DOI: 10.1038/s41586-024-08346-4

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