The Role of Monoallelic Expression in Incomplete Penetrance of Primary Immunodeficiencies

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Project Summary: Primary immunodeficiencies (PIDs) are monogenic disorders of the immune system. PIDs affect 1 in 780 hospitalized children. Incomplete penetrance of PIDs is common and remains largely unexplained. Herein I hypothesize that incomplete penetrance in PIDs may also be explained by monoallelic expression (MAE). Traditionally, transcription of autosomal genes is thought to occur from both inherited genes. Recent studies indicate that up to 10% of autosomal genes can randomly commit to gene expression from a single allele, termed monoallelic expression. Unlike X-inactivation or imprinting, MAE is independent of other genes and leads to a diverse population of cells at the transcript level. The existence of MAE of PID genes is unknown. Families with mutations in JAK1 or PLCG2 exhibit incomplete disease penetrance. My preliminary data suggests that both JAK1 and PLCG2 can undergo MAE. Within this proposal I aim to 1) Map MAE of PID genes in primary immune cells and 2) evaluate the functional impact of monoallelic expression in JAK1 and PLCG2 ex vivo. The findings of this proposal will inform the biological study and clinical genetics of PIDs by identifying thresholds of transcript diversity which drive disease penetrance. In addition, these findings will provide a framework for similar work in other genetic diseases, while setting a foundation for mechanistic studies directed at the control of MAE as a therapeutic for monogenic disease.