Large deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome

Abstract

Background: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused at least in part by haploinsufficiency of the SHANK3 gene, due to sequence variants in SHANK3 or subtelomeric 22q13.3 deletions. Divergent phenotypic profiles have been reported between PMS participants with Class I mutations, defined as sequence variants or small deletions, including SHANK3 only or SHANK3 with ARSA and/or ACR and RABL2B, and those with Class II mutations, defined as those with larger 22q13.3 deletions. The molecular perturbations that underlie these divergent phenotypes remain poorly understood. Methods: Peripheral blood transcriptomic profiling was performed across 68 PMS participants, including Class I mutations (n=33) and Class II mutations (n=35), as well as an age and sex matched control group (n=24). In parallel, global serum metabolomic profiling was carried out across a subset of 25 participants, comprised of Class I mutations (n=11), Class II mutations (n=14), and an age and sex matched control group (n=29). Results: Transcriptomic data revealed 52 blood expressed genes on 22q13.3 with expression profiles that scaled with the size of Class II mutations, including expression for genes ARSA, BRD1 and RPP7A. Further analyses uncovered 208 under-expressed genes and 42 over-expressed genes in participants with Class II mutations relative to unaffected controls, which were unchanged in PMS participants with Class I mutations. These genes were not linked to 22q13.3, and under-expressed genes were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions and cytotoxic immune cell signatures. Reductions in proportions of CD56+ CD16- natural killer cells in Class II mutations were confirmed by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered with PMS participants with Class II mutations, and featured a general reduction in sphingolipid metabolism. Conclusions: Our results provide evidence for transcriptomic and metabolomic perturbations in the peripheral circulation of PMS participants with Class II mutations that implicate reduced frequency and expression of natural killer cells and related signatures and lower sphingolipid metabolism. These findings are a valuable resource for future studies examining peripheral biomarkers and immuno-genetics of PMS and other rare disorders.