Autosomal recessive mutations in G6PC3 cause isolated and syndromic congenital neutropenia which includes congenital heart disease and atypical inflammatory bowel disease (IBD). In a highly consanguineous pedigree with novel mutations in G6PC3 and MPL, we performed comprehensive multi-omics analyses. Structural analysis of variant G6PC3 and MPL proteins suggests a damaging effect. A distinct molecular cytokine profile (cytokinome) in the affected proband with IBD was detected. Liquid chromatography-mass spectrometry-based proteomics analysis of the G6PC3 deficient plasma samples identified 460 distinct proteins including 75 upregulated and 73 downregulated proteins. Specifically, the transcription factor GATA4 and LST1 were downregulated while platelet factor 4 (PF4) was upregulated. GATA4 and PF4 have been linked to congenital heart disease and IBD respectively, while LST1 may have perturbed a variety of essential cell functions as it is required for normal cell-cell communication. Together, these studies provide potentially novel insights into the pathogenesis of syndromic congenital G6PC3 deficiency.