Study of inborn errors of immunity associated lymphoid proliferations identifies association of presence of somatic variations with large cell morphology, copy number alterations in TNFAIP3 and heterozygous variants in EMSY.

Lymphoproliferative disorders (LPDs) associated with inborn errors of immunity (IEI) are rare entities and their genetic basis is not well defined. We performed targeted deep sequencing using a panel of 529 genes to investigate the single nucleotide variants (SNVs), insertion/deletions (INDELs), structural rearrangements (SVs), and copy number variants (CNVs) in 16 lymphoproliferations associated with IEI belonging to a cohort of 14 patients. Histomorphologically, the cases were classified into B-cell hyperplasia (n = 1); polymorphic B-lymphoproliferative disorder (n = 8); polymorphic B-lymphoproliferative disorder with focal increased large cell component bordering large B cell lymphoma (n = 3); and large B-cell lymphoma (n = 4). Fourteen of the 16 cases were EBV positive. Across the patients, 40 variants were identified. The majority of the genes affected were those involved in DNA damage response pathways and transcriptional regulation. Pathogenic SNVs, INDELs, and CNVs were increased in cases with a large B cell component vs other cases. Heterozygous SNVs in protein interaction domains of EMSY were identified in 3 cases, suggesting that it may have a predisposing role in the development of lymphoproliferations. Deletions involving the TNFAIP3 gene (copy number losses) were also recurrent, identified in 3 of 16 cases (18.8%) and correlated with large cell morphology.