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Cited by 2Genetics and Neurodevelopmental DisordersAutism Spectrum Disorder ResearchGenomics and Rare Diseases

SHANK3 deficiency alters early progenitor dynamics and reveals shared pathways with neurodegeneration

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Varella-Branco, Elisa, Shephard, Elizabeth, Toledo, Victor H. C., Ramos, Igor C., Lacerda, Ellen C. M., Carvalho, Laura L. M., Fiuza, Marcella A., Paschalidis, Mayara +10 more·2026·Molecular Psychiatry
DOI 10.1038/s41380-025-03433-yPMC PMC13190290
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Abstract

Phelan-McDermid Syndrome (PMS), primarily linked to SHANK3 haploinsufficiency, presents with complex neurodevelopmental features, including developmental regression, whose underlying mechanisms are poorly understood. This study investigated the impact of SHANK3 disruption across multiple levels, from gene expression in patient-derived iPSC neurons to in vivo brain network activity. RNA-sequencing of iPSC-derived neurons from PMS patients with SHANK3 disruption only (n = 9) and controls (n = 7) revealed dysregulation in differential gene expression and co-expression modules linked to cell cycle, RNA metabolism, and metabolic pathways in SHANK3 -mutated neurons. All modules were correlated with PMS regression and enriched for genes implicated in neurodevelopmental or neurodegenerative disorders, such as autism, ADHD, and Alzheimer’s disease. At the cellular level, SHANK3 -mutated cultures exhibited increased proliferation of neural progenitors and intermediate progenitor markers. Differentiated neurons showed reduced morphological complexity, specific changes in postsynaptic marker density and puncta size, and electrophysiological characteristics suggestive of neuronal hyperexcitability. Electroencephalography (EEG) in a PMS patient cohort (n = 20) compared to controls (n = 30) demonstrated hyperconnectivity and excessive high-frequency oscillations, suggesting altered neural network dynamics. In summary, the use of different analytical approaches suggested that SHANK3 haploinsufficiency disrupts neurodevelopmental trajectories and revealed that regression in PMS may share common genes and pathways with neurodegeneration. We also characterized molecular and neurophysiological markers that can be useful in therapeutic protocols for PMS.

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  • Haploinsufficiency of SHANK3 is commonly associated with Phelan-McDermid syndrome and broad developmental impairments, whereas specific missense variants may produce more restricted or clinically variable synaptic phenotypes.

    “Similarly, haploinsufficiency of SHANK3 is commonly associated with Phelan-McDermid syndrome and broad developmental impairments, whereas specific missense variants may produce more restricted or clinically variable synaptic phenotypes”

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

    The Introduction (page unavailable) links SHANK3 disruption to Phelan-McDermid syndrome and describes its developmental impairments; the Abstract explicitly identifies SHANK3 haploinsufficiency as a primary link. The paper does not establish the claimed contrast with missense variants producing more restricted or clinically variable synaptic phenotypes. Its missense-related mention appears only in a reference title. (LLM, conf=0.88)

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Authors
Varella-Branco, E., Shephard, E., Toledo, V. H. C., Ramos, I. C., Lacerda, E. C. M., Carvalho, L. L. M., Fiuza, M. A., Paschalidis, M., Costa, C. I. S., Girardi, A. C. S., Krepischi, A. C. V., Casella, E. B., Polanczyk, G., Griesi-Oliveira, K., Papes, F., Alvizi, L., Kobayashi, G. S., & dos Santos e Passos Bueno, M. R.
Affiliations
  • Universidade de São Paulo (BR)
  • University College London (GB)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2026-01-31
Volume
31
Issue
6
Pages
3033-3048
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-025-03433-y
PMC
PMC13190290
OpenAlex
W7126461991
Cited by
2
References
10
Citations by year
2026: 2
FWCI
8.01
Type
journal article
Language
en
Open access
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  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
  • Fundação de Amparo à Pesquisa do Estado de São Paulo (13/08028-1, 08028-1, 2013/ 08028-1, 2013/08028, 88887, 2020/13355-5)
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (2013/08028-1, 88887, 00x0MA614, 2020-00, 303712/2016-3)
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (466651/2014‐7, 2013/08028-1, 303712/2016‐3)
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 › Genomics and Rare Diseases
Keywords
Phelan-McDermid syndrome, developmental regression, neural progenitor proliferation, intermediate progenitor cells, iPSC-derived neurons, gene expression dysregulation, neuronal hyperexcitability, postsynaptic density, high-frequency oscillations, neurodevelopmental disorders, neurodegeneration, autism spectrum disorder, Alzheimer's disease
MeSH terms
Neurodevelopment, Adolescent, Adult, Brain, Cell Differentiation, Child, Chromosome Deletion, Chromosomes, Human, Pair 22, Electroencephalography, Female, Humans, Male, Mutation, Nerve Tissue Proteins, Neurons, Neurodegenerative Diseases, Chromosome Disorders, Induced Pluripotent Stem Cells, Haploinsufficiency, Neural Stem Cells

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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