Table 2.

Summary of preclinical and clinical Shank3/PMD studies characterising behavioural and brain phenotypes.

	iPSC	Murine model	Human
Clinical/behavioural phenotype	N/A	↑ Repetitive self- grooming (Wang et al., 2011; Yoo et al., 2019; Matas et al., 2021; Ferhat et al., 2023) ↓ Ultrasonic vocalisations (Peça et al., 2011) ↑Persistence in unsuccessful social partner engagement (Wang X. et al., 2016) ↓Sociability and interaction (Peça et al., 2011; Orefice et al., 2019), and no difference in social preference (Drapeau et al., 2018) or social recognition (Kabitzke et al., 2018) ↓Investigatory behaviour (Wang X. et al., 2016) Avoidance to novelty (Wang X. et al., 2016) ↑Anxiety (Wang X. et al., 2016; Bey et al., 2018; Drapeau et al., 2018) ↓ Sensory motor gating and ↓motor learning (Bey et al., 2018; Drapeau et al., 2018; Yoo et al., 2019) ↓ Recognition memory (Wang et al., 2011) ↓Spatial learning (Wang X. et al., 2016, Drapeau et al., 2018) ↓Striatal-dependent instrumental learning (Wang X. et al., 2016) Sleep problems (Ingiosi et al., 2019, Medina et al., 2022)	Clinical diagnosis: Neonatal hypotonia, delayed motor milestones, delayed or absent speech, intellectual disability, autism (Phelan et al., 1993; Phelan and McDermid, 2011; Kolevzon et al., 2014) Bipolar disorder and Psychosis symptom presentations (Kolevzon et al., 2019; Vogels et al., 2021) Sensory stimulating behaviours (Phelan and McDermid, 2011) and sensory reactivity (Tavassoli et al., 2021) ↓ Pain perception (Phelan and McDermid, 2011) ↑ Sleep problems (Bro et al., 2017; Smith-Hicks et al., 2021) ↓ Recognition memory and altered attentional engagement (Guillory et al., 2021)
Brain phenotype	↓ Glutamate receptor expression and synapse number in forebrain neurons (Shcheglovitov et al., 2013) ↓ Dendritic outgrowth in cortical neurons (Kathuria et al., 2018) ↓ Excitatory synapse number, ↓dendritic spines and outgrowth in cortical neurons transplanted into mice prefrontal cortex (Chiola et al., 2021) Hyperpolarisation channelopathy phenotype in human ESC cortical neuron (Yi et al., 2016)	Cortico-striatal hyperactivity (Peixoto et al., 2016) Cortico-amygdala hyperactivity (Kim et al., 2022) ↓ Hippocampal NMDA/AMPA excitatory ratio (Kouser et al., 2013) ↓ Excitatory transmission in hippocampal CA1, ↓ inhibitory synaptic events in medial prefrontal cortex (Lee et al., 2015) ↑ Spontaneous and stimulus-evoked activity of excitatory neurons in somatosensory cortex and ↓ interneuron activity (Chen et al., 2020) MRS: ↓glutamate concentration in striatum sMRI: ↓ total brain (Ellegood et al., 2015; Schoen et al., 2019), ↓ hippocampal (Schoen et al., 2019), and prefrontal cortex volume (Pagani et al., 2019), and ↑ Increased striatum volume (Peça et al., 2011; Wang X. et al., 2016) DTI: ↓ white matter microstructural architecture in external capsule (Golden et al., 2021), fronto-occipital association fibers and motor cortex-entorhinal cortex tract (Jesse et al., 2020)	Epilepsy/seizures (Kolevzon et al., 2019) EEG: ↓ VEP amplitude (Siper et al., 2022) EEG: Preserved auditory neural response and habituation; auditory processing variability linked to genetic subtype(Isenstein et al., 2022) EEG: ↑ phase amplitude coupling phase bias in posterior brain regions (Mariscal et al., 2021) fMRI: ↑activity for communicative sounds in the right superior temporal gyrus (Wang A. T. et al., 2016) sMRI: ↓ total brain vol, basal ganglia, and cerebellum in some studies DTI: ↓ corpus callosum white matter, and overall white matter thinning and altered uncinate fasciculus, inferior fronto-occipital fasciculus, and corticostriatal tract (Jesse et al., 2020)