Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome
Michael S. Breen,
Xuanjia Fan,
Tess Levy,
Rebecca M. Pollak,
Brett Collins,
Aya Osman,
Anna S. Tocheva,
Mustafa Sahin,
Elizabeth Berry-Kravis,
Latha Soorya,
Audrey Thurm,
Craig M. Powell,
Jonathan A. Bernstein,
Alexander Kolevzon,
Joseph D. Buxbaum,
Simon K. Warfield,
Benoit Scherrer,
Rajna Filip-Dhima,
Kira Dies,
Paige Siper,
Ellen Hanson,
Jennifer M. Phillips
Affiliations
Michael S. Breen
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Corresponding author
Xuanjia Fan
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Tess Levy
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Rebecca M. Pollak
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Brett Collins
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Aya Osman
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Anna S. Tocheva
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Mustafa Sahin
Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA; Rosamund Stone Zander Translational Neuroscience Center and F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
Elizabeth Berry-Kravis
Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
Latha Soorya
Department of Psychiatry, Rush University Medical Center, Chicago, IL, USA
Audrey Thurm
Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA
Craig M. Powell
Department of Neurobiology, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA; Civitan International Research Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
Jonathan A. Bernstein
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
Alexander Kolevzon
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Joseph D. Buxbaum
Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Corresponding author
Summary: 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. Phenotypic differences have been reported between PMS participants carrying small “class I” mutations and large “class II” mutations; however, the molecular perturbations underlying these divergent phenotypes remain obscure. Using peripheral blood transcriptome and serum metabolome profiling, we examined the molecular perturbations in the peripheral circulation associated with a full spectrum of PMS genotypes spanning class I (n = 37) and class II mutations (n = 39). Transcriptomic data revealed 52 genes with blood expression profiles that tightly scale with 22q.13.3 deletion size. Furthermore, we uncover 208 underexpressed genes in PMS participants with class II mutations, which were unchanged in class I mutations. These genes were not linked to 22q13.3 and were strongly enriched for glycosphingolipid metabolism, NCAM1 interactions, and cytotoxic natural killer (NK) immune cell signatures. In silico predictions estimated a reduction in CD56+ CD16– NK cell proportions in class II mutations, which was validated by mass cytometry time of flight. Global metabolomics profiling identified 24 metabolites that were significantly altered in PMS participants with class II mutations and confirmed a general reduction in sphingolipid metabolism. Collectively, these results provide new evidence linking PMS participants carrying class II mutations with decreased expression of cytotoxic cell signatures, reduced relative proportions of NK cells, and lower sphingolipid metabolism. These findings highlight alternative avenues for therapeutic development and offer new mechanistic insights supporting genotype-to-phenotype associations in PMS.
