Journal Article

DZNE-2026-00337

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png SHANK3 and beta-synuclein are novel blood-based biomarkers for the Phelan-McDermid Syndrome: a pilot study.

Pagano, J. ; Perez Arevalo, A. ; Nosanova, A. ; Bauer, H. F. ; Loth, E. ; Andres, S. ; Becker, F. ; Otto, M. ; Stefanoni, A. ; Verpelli, C.DZNE* ; Oeckl, P.DZNE* ; Schön, M. ; Boeckers, T. (Last author)DZNE*

2026
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/s41398-026-03932-8

Abstract: Phelan-McDermid syndrome (PMS) is a relatively frequent cause of syndromic intellectual disability (ID) and autism spectrum disorder (ASD). It is typically caused by genetic alterations in the 22q13 chromosomal region, most often involving heterozygous deletions or mutations in the SHANK3 gene. More than half of affected individuals exhibit functional impairments in speech, cognition, motor skills, and behavior. Despite multiple ongoing therapeutic programs, objective and scalable liquid biomarkers to support patient stratification and to monitor disease course or treatment response are still lacking. Here, in a pilot study involving 23 individuals with PMS, we identified two biomarkers that are significantly altered compared to a control group and are associated with symptom severity. First, SHANK3 protein was detectable in peripheral blood mononuclear cells (PBMCs) and was markedly reduced in PMS (mean -77% vs. controls), consistent with SHANK3 haploinsufficiency; lower PBMC SHANK3 levels were associated with the presence of developmental regression, supporting its potential utility as a target-engagement/monitoring biomarker rather than a diagnostic screen. Additionally, plasma levels of beta-synuclein, a neuron-specific synaptic protein, were elevated in PMS and positively correlated with the severity of speech impairment. Both biomarkers were successfully back-translated in a Shank3 transgenic mouse model, where beta-synuclein levels were normalized through modulation of the mGlu5 receptor. Together, these results provide initial evidence for SHANK3 in PBMCs and plasma beta-synuclein as complementary liquid biomarkers to aid prognosis and enable objective monitoring of therapeutic response in PMS, warranting validation in larger and pediatric longitudinal cohorts.

Keyword(s): Humans (MeSH) ; Pilot Projects (MeSH) ; Biomarkers: blood (MeSH) ; Male (MeSH) ; Female (MeSH) ; Chromosome Disorders: blood (MeSH) ; Chromosome Disorders: genetics (MeSH) ; Chromosome Disorders: diagnosis (MeSH) ; Nerve Tissue Proteins: blood (MeSH) ; Nerve Tissue Proteins: genetics (MeSH) ; Chromosomes, Human, Pair 22: genetics (MeSH) ; Chromosome Deletion (MeSH) ; Child (MeSH) ; Adolescent (MeSH) ; Adult (MeSH) ; Leukocytes, Mononuclear: metabolism (MeSH) ; Child, Preschool (MeSH) ; Young Adult (MeSH) ; Case-Control Studies (MeSH) ; Biomarkers ; SHANK3 protein, human ; Nerve Tissue Proteins

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Contributing Institute(s):

1. Translational Protein Biochemistry (AG Böckers)
2. Translational Mass Spectrometry and Biomarker Research (AG Öckl)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
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