Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.<b>SIGNIFICANCE STATEMENT</b> Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits.
De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID).
Mutation in the SHANK3 human gene leads to different neuropsychiatric diseases including Autism Spectrum Disorder (ASD), intellectual disabilities and Phelan-McDermid syndrome.
Deletions and point mutations in SHANK3 cause Phelan-McDermid Syndrome (PMS), and have also been implicated in autism spectrum disorder (ASD) and intellectual disabilities, leading to the hypothesis that reduced SHANK3 expression impairs basic brain functions that are important for social communication and cognition.
Furthermore, a significant number of SHANK3 mutations have been identified in patients with autism spectrum disorders (ASD), and SHANK3 truncating mutations are associated with moderate to profound ID.
The most common semiology is atypical absence seizure, which can be challenging to identify due to comorbid intellectual disability in individuals with SHANK3 mutations; however, no consistent seizure semiology, neuroimaging findings, or EEG findings were present in the majority of individuals with SHANK3 mutations.
Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1.
Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.
In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.
Shank/ProSAP proteins are major scaffold proteins of the postsynaptic density; mutations in the human SHANK3 gene are associated with intellectual disability or autism spectrum disorders.
We report two children with interstitial deletions of 22q13 and two copies of SHANK3, but clinical features similar to the terminal 22q13 deletion syndrome, including mental retardation and severe speech delay.
Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech.
Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech.
Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech.