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Cited by 2Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomic variations and chromosomal abnormalities

SHANK3 and beta-synuclein are novel blood-based biomarkers for the Phelan-McDermid syndrome: a pilot study

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Pagano, Jessica, Perez Arevalo, Andrea, Nosanova, Anastasia, Bauer, Helen Friedericke, Loth, Eva, Andres, Stephanie, Becker, Felicitas, Otto, Markus +5 more·2026·Translational Psychiatry
DOI 10.1038/s41398-026-03932-8PMC PMC13039877
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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.

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  • SHANK3 haploinsufficiency underpins Phelan-McDermid syndrome, characterized by ASD alongside severe language deficits, neonatal hypotonia, and other developmental abnormalities.

    “Conversely, SHANK3 haploinsufficiency underpins Phelan-McDermid syndrome, characterized by ASD alongside severe language deficits, neonatal hypotonia, and other developmental abnormalities (Pagano et al., 2026).”

    From Biological hierarchy from genotype to phenotype in syndromic and non-syndromic autism spectrum disorder (2026) · cites this paper as Pagano et al., 2026

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  1. [1]Phelan K, McDermid HE. The 22q13.3 deletion syndrome (Phelan-McDermid syndrome). Mol Syndromol. 2012;2:186–201. 22670140 PMC3366702 · DOI · Paper page
  2. [2]Phelan MC, Rogers RC, Saul RA, Stapleton GA, Sweet K, McDermid H, et al. 22q13 deletion syndrome. Am J Med Genet. 2001;101:91–9. 11391650 · DOI
  3. [3]Denayer A, Van Esch H, de Ravel T, Frijns JP, Van Buggenhout G, Vogels A, et al. Neuropsychopathology in 7 patients with the 22q13 deletion syndrome: presence of bipolar disorder and progressive loss of skills. Mol Syndromol. 2012;3:14–20. 22855650 PMC3398818 · DOI · Paper page
  4. [4]Vitrac A, Leblond CS, Rolland T, Cliquet F, Mathieu A, Maruani A, et al. Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome. Eur J Med Genet. 2023;66:104732. 36822569 · DOI
  5. [5]Koza SA, Tabet AC, Bonaglia MC, Andres S, Anderlid BM, Aten E, et al. Consensus recommendations on counselling in Phelan-McDermid syndrome, with special attention to recurrence risk and to ring chromosome 22. Eur J Med Genet. 2023;66:104773. 37120077 · DOI
  6. [6]Disciglio V, Lo Rizzo C, Mencarelli MA, Mucciolo M, Marozza A, Di Marco C, et al. Interstitial 22q13 deletions not involving SHANK3 gene: a new contiguous gene syndrome. Am J Med Genet A. 2014;164A:1666–76. 24700646 · DOI
  7. [7]Simenson K, Õiglane-Shlik E, Teek R, Kuuse K, Õunap K. A patient with the classic features of Phelan-McDermid syndrome and a high immunoglobulin E level caused by a cryptic interstitial 0.72-Mb deletion in the 22q13.2 region. Am J Med Genet A. 2014;164:806–9. 24375995 · DOI
  8. [8]Li S, Xi KW, Liu T, Zhang Y, Zhang M, Zeng LD, et al. Fraternal twins with Phelan-McDermid syndrome not involving the SHANK3 gene: case report and literature review. BMC Med Genomics. 2020;13:146. 33023580 PMC7539423 · DOI
  9. [9]Wilson HL, Crolla JA, Walker D, Artifoni L, Dallapiccola B, Takano T, et al. Interstitial 22q13 deletions: genes other than SHANK3 have major effects on cognitive and language development. Eur J Hum Genet. 2008;16:1301–10. 18523453 · DOI · Paper page
  10. [10]Phelan K, Boccuto L, Powell CM, Boeckers TM, van Ravenswaaij-Arts C, Rogers RC, et al. Phelan-McDermid syndrome: a classification system after 30 years of experience. Orphanet J Rare Dis. 2022;17:27. 35093143 PMC8800328 · DOI
  11. [11]Roussignol G, Ango F, Romorini S, Tu JC, Sala C, Worley PF, et al. Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci. 2005;25:3560–70. 15814786 PMC6725374 · DOI · Paper page
  12. [12]Sala C, Vicidomini C, Bigi I, Mossa A, Verpelli C. Shank synaptic scaffold proteins: keys to understanding the pathogenesis of autism and other synaptic disorders. J Neurochem. 2015;135:849–58. 26338675 · DOI
  13. [13]Sheng M, Kim E. The Shank family of scaffold proteins. J Cell Sci. 2000;113:1851–56. 10806096 · DOI · Paper page
  14. [14]Malara M, Lutz AK, Incearap B, Bauer HF, Cursano S, Volbracht K, et al. SHANK3 deficiency leads to myelin defects in the central and peripheral nervous system. Cell Mol Life Sci. 2022;79:371. 35726031 PMC9209365 · DOI
  15. [15]Jesse S, Müller HP, Schoen M, Asoglu H, Bockmann J, Huppertz HJ, et al. Severe white matter damage in SHANK3 deficiency: a human and translational study. Ann Clin Transl Neurol. 2020;7:46–58. 31788990 PMC6952316 · DOI
  16. [16]Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39:25–7. 17173049 PMC2082049 · DOI · Paper page
  17. [19]Schön M, Lapunzina P, Nevado J, Mattina T, Gunnarsson C, Hadzsiev K, et al. Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome. Eur J Med Genet. 2023;66:104754. 37003575 · DOI
  18. [20]Bauer HF, Delling JP, Bockmann J, Boeckers TM, Schön M. Development of sex- and genotype-specific behavioral phenotypes in a Shank3 mouse model for neurodevelopmental disorders. Front Behav Neurosci. 2022;16:1051175. 36699652 PMC9868822 · DOI
  19. [21]Oeckl P, Mayer B, Bateman RJ, Day GS, Fox NC, Huey ED, et al. Early increase of the synaptic blood marker β-synuclein in asymptomatic autosomal dominant Alzheimer’s disease. Alzheimers Dement. 2025;21:e70146. 40207431 PMC11982912 · DOI
  20. [22]Oeckl P, Halbgebauer S, Anderl-Straub S, von Arnim CAF, Diehl-Schmid J, Froelich L, et al. Targeted mass spectrometry suggests beta-synuclein as synaptic blood marker in Alzheimer’s disease. J Proteome Res. 2020;19:1310–8. 32101007 · DOI
  21. [23]Oeckl P, Janelidze S, Halbgebauer S, Stomrud E, Palmqvist S, Otto M, et al. Higher plasma β-synuclein indicates early synaptic degeneration in Alzheimer’s disease. Alzheimers Dement. 2023;19:5095–102. 37186338 · DOI
  22. [24]Oeckl P, Anderl-Straub S, Danek A, Diehl-Schmid J, Fassbender K, Fliessbach K, et al. Relationship of serum beta-synuclein with blood biomarkers and brain atrophy. Alzheimers Dement. 2023;19:1358–71. 36129098 · DOI
  23. [25]Barba L, Abu Rumeileh S, Bellomo G, Paolini Paoletti F, Halbgebauer S, Oeckl P, et al. Cerebrospinal fluid β-synuclein as a synaptic biomarker for preclinical Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2023;94:83–6. 35944974 · DOI
  24. [26]Giona F, Beretta S, Zippo A, Stefanoni A, Tomasoni Z, Vicidomini C, et al. Shank3 modulates Rpl3 expression and protein synthesis via mGlu5: implications for Phelan McDermid syndrome. Mol Psychiatry. 2025;30:3599–614. 10.1038/s41380-025-02947-9. 40089604 PMC12240844 · DOI
  25. [27]Vicidomini C, Ponzoni L, Lim D, Schmeisser MJ, Reim D, Morello N, et al. Pharmacological enhancement of mGlu5 receptors rescues behavioral deficits in SHANK3 knock-out mice. Mol Psychiatry. 2017;22:689–702. 27021819 PMC5014121 · DOI
  26. [28]Cammarata-Scalisi F, Callea M, Martinelli D, Willoughby CE, Cárdenas Tadich A, Araya Castillo M, et al. Clinical and genetic aspects of Phelan-McDermid syndrome: an interdisciplinary approach to management. Genes. 2022;13:504. 35328058 PMC8955098 · DOI
  27. [29]Peters DG, Yatsenko SA, Surti U, Rajkovic A. Recent advances of genomic testing in perinatal medicine. Semin Perinatol. 2015;39:44–54. 25444417 PMC4883661 · DOI
  28. [30]Stessman HA, Bernier R, Eichler EE. A genotype-first approach to defining the subtypes of a complex disease. Cell. 2014;156:872–77. 24581488 PMC4076166 · DOI
  29. [32]Loth E, Spooren W, Ham LM, Isaac MB, Auriche-Benichou C, Banaschewski T, et al. Identification and validation of biomarkers for autism spectrum disorders. Nat Rev Drug Discov. 2016;15:70–3. 26718285 · DOI · Paper page
  30. [33]Sahin M, Sweeney JA, Jones SR. Editorial: biomarkers to enable therapeutics development in neurodevelopmental disorders. Front Integr Neurosci. 2020;14:616641. 33262695 PMC7686575 · DOI
  31. [34]Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2006;141B:261–68. 16526044 · DOI
  32. [35]Rollins B, Martin MV, Morgan L, Vawter MP. Analysis of whole genome biomarker expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:919–36. 20127885 PMC3098564 · DOI
  33. [36]Nardo G, Pozzi S, Pignataro M, Lauranzano E, Spano G, Garbelli S, et al. Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells. PLoS One. 2011;6:e25545. 21998667 PMC3187793 · DOI
  34. [37]Pansarasa O, Garofalo M, Scarian E, Dragoni F, Garau J, Di Gerlando R, et al. Biomarkers in human peripheral blood mononuclear cells: the state of the art in amyotrophic lateral sclerosis. Int J Mol Sci. 2022;23:2580. 35269723 PMC8910056 · DOI
  35. [38]Kleiveland CR Peripheral blood mononuclear cells. In: Verhoeckx K, Cotter P, López-Expósito I, Kleiveland C, Lea T, Mackie A et al. eds. The Impact of Food Bioactives on Health: In Vitro and Ex Vivo Models. Cham: Springer, 2015:pp. 161–67. 29787039
  36. [39]Redecker P, Bockmann J, Böckers TM. Expression of postsynaptic density proteins of the ProSAP/Shank family in the thymus. Histochem Cell Biol. 2006;126:679–85. 16758162 · DOI
  37. [40]De Rubeis S, Siper PM, Durkin A, Weissman J, Muratet F, Halpern D, et al. Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. Mol Autism. 2018;9:31. 29719671 PMC5921983 · DOI
  38. [41]Dhar SU, del Gaudio D, German JR, Peters SU, Ou Z, Bader PI, et al. 22q13.3 deletion syndrome: clinical and molecular analysis using array CGH. Am J Med Genet A. 2010;152A:573–81. 20186804 PMC3119894 · DOI · Paper page
  39. [42]Samogy-Costa CI, Varella-Branco E, Monfardini F, Ferraz H, Fock RA, Barbosa RHA, et al. A Brazilian cohort of individuals with Phelan-McDermid syndrome: genotype-phenotype correlation and identification of an atypical case. J Neurodev Disord. 2019;11:13. 31319798 PMC6637483 · DOI
  40. [43]Xu N, Lv H, Yang T, Du X, Sun Y, Xiao B, et al. A 29 Mainland Chinese cohort of patients with Phelan-McDermid syndrome: genotype-phenotype correlations and the role of SHANK3 haploinsufficiency in the important phenotypes. Orphanet J Rare Dis. 2020;15:335. 33256793 PMC7708101 · DOI
  41. [44]Soorya L, Leon J, Trelles MP, Thurm A. Framework for assessing individuals with rare genetic disorders associated with profound intellectual and multiple disabilities (PIMD): the example of Phelan McDermid syndrome. Clin Neuropsychol. 2018;32:1226–55. 29265961 PMC6417924 · DOI
  42. [45]Breen MS, Fan X, Levy T, Pollak RM, Collins B, Osman A, et al. Large 22q13.3 deletions perturb peripheral transcriptomic and metabolomic profiles in Phelan-McDermid syndrome. HGG Adv. 2022;4:100145. 36276299 PMC9579712
  43. [46]Oeckl P, Metzger F, Nagl M, von Arnim CAF, Halbgebauer S, Steinacker P, et al. Alpha-, beta-, and gamma-synuclein quantification in cerebrospinal fluid by multiple reaction monitoring reveals increased concentrations in Alzheimer’s and Creutzfeldt-Jakob disease but no alteration in synucleinopathies. Mol Cell Proteom. 2016;15:3126–38. PMC5054339 27507836 · DOI
  44. [47]Bergström S, Remnestål J, Yousef J, Olofsson J, Markaki I, Carvalho S, et al. Multi-cohort profiling reveals elevated CSF levels of brain-enriched proteins in Alzheimer’s disease. Ann Clin Transl Neurol. 2021;8:1456–70. 34129723 PMC8283172 · DOI
  45. [48]Halbgebauer S, Oeckl P, Steinacker P, Yilmazer-Hanke D, Anderl-Straub S, von Arnim C, et al. Beta-synuclein in cerebrospinal fluid as an early diagnostic marker of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2021;92:349–56. 33380492 · DOI
  46. [49]Reierson G, Bernstein J, Froehlich-Santino W, Urban A, Purmann C, Berquist S, et al. Characterizing regression in Phelan McDermid syndrome (22q13 deletion syndrome). J Psychiatr Res. 2017;91:139–44. 28346892 PMC5469716 · DOI
  47. [50]Kohlenberg TM, Trelles MP, McLarney B, Betancur C, Thurm A, Kolevzon A. Psychiatric illness and regression in individuals with Phelan-McDermid syndrome. J Neurodev Disord. 2020;12:7. 32050889 PMC7014655 · DOI
  48. [51]van Ravenswaaij-Arts CMA, van Balkom IDC, Jesse S, Bonaglia MC. Editorial: Towards a European consensus guideline for Phelan-McDermid syndrome. Eur J Med Genet. 2023;66:104736. 36907549 · DOI
  49. [52]Srivastava S, Sahin M, Buxbaum JD, Berry-Kravis E, Soorya LV, Thurm A, et al. Updated consensus guidelines on the management of Phelan-McDermid syndrome. Am J Med Genet A. 2023;191:2015–44. 37392087 PMC10524678 · DOI

Cited by

Sorted by citations

Authors
Pagano, J., Perez Arevalo, A., Nosanova, A., Bauer, H. F., Loth, E., Andres, S., Becker, F., Otto, M., Stefanoni, A., Verpelli, C., Oeckl, P., Schön, M., & Boeckers, T.
Affiliations
  • Universität Ulm (DE)
  • King's College London (GB)
  • Medicover (DE)
  • German Center for Neurodegenerative Diseases (DE)
Corresponding author
  • Schön, Michael
  • Boeckers, Tobias
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2026-03-24
Volume
16
Issue
1
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-026-03932-8
PMC
PMC13039877
OpenAlex
W7140226457
Cited by
2
References
3
Citations by year
2026: 2
FWCI
8.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DZNE Pub (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Digitalen Hochschulbibliothek Sachsen-Anhalt (Universitäts- und Landesbibliothek Sachsen-Anhalt) (cc-by)
Funders
Deutsche Forschungsgemeinschaft (CRC1149, CRC 1506)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
Phelan-McDermid syndrome, SHANK3, beta-synuclein, liquid biopsy biomarkers, peripheral blood mononuclear cells, plasma biomarkers, syndromic intellectual disability, autism spectrum disorder, 22q13 deletion, developmental regression, speech disorders, mGlu5 receptor, treatment response monitoring
MeSH terms
Adolescent, Adult, Animals, Child, Child, Preschool, Chromosome Deletion, Chromosomes, Human, Pair 22, Female, Humans, Leukocytes, Mononuclear, Male, Microfilament Proteins, Nerve Tissue Proteins, Pilot Projects, Biomarkers, Case-Control Studies, Chromosome Disorders, Mice, Young Adult

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