SHANK3

The SHANK3 gene provides the blueprint for a protein found throughout the body, with its highest levels in the brain. This protein plays a central role at synapses—the junctions where neurons communicate—by acting as a structural scaffold that helps maintain strong, efficient connections between nerve cells.

SHANK3 also contributes to the development and shaping of dendritic spines, the small branches that grow off neurons to increase communication and signal transmission.

SHANK3 mutations include a variety of changes that disrupt the protein’s function:

• Deletions and chromosomal rearrangements involving SHANK3—especially in the 22q13 region (Phelan-McDermid syndrome)—result in the loss of one copy of the gene (haploinsufficiency).
• Intragenic point mutations (such as nonsense, frameshift, or splice-site alterations) within SHANK3 cause truncation or loss of essential protein domains .
• Missense mutations have been identified in several key functional regions (e.g., SPN, ankyrin, PDZ, SAM domains). Their effects on protein function are highly variable, but some have been linked to impaired synapse formation in cellular models

• Phelan-McDermid syndrome (PMS) is estimated to affect 1 in 8,000–20,000 individuals worldwide. Over 1,200 cases have been confirmed, though diagnosis is likely underreported due to access limitations 
• SHANK3 mutations/deletions occur in approximately 0.5–2% of individuals with autism spectrum disorder (ASD), with higher rates (~2%) among ASD cases also involving intellectual disability 
• In a focused study, 2.3% of ASD patients had pathogenic SHANK3 variants, including frame-shifts, splice-site changes, and deletions.

22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome)
A deletion involving the SHANK3 gene can lead to this neurodevelopmental condition. Individuals typically have only one copy of SHANK3 instead of the usual two, which disrupts synaptic communication. Common features include developmental delay, intellectual disability, low muscle tone, and severely delayed or absent speech.

Autism Spectrum Disorder (ASD)
At least 43 mutations in SHANK3 have been identified in individuals with autism. These changes often impair or block SHANK3 protein production, which can interfere with neuron signaling. Although the link is not yet fully understood, SHANK3 disruptions are believed to contribute to core features of ASD, such as social and communication challenges and repetitive behaviors.

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.

Boccuto L, Lauri M, Sarasua SM, Skinner CD, Buccella D, Dwivedi A, et al.
Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders.

Phelan K, McDermid HE.
The 22q13.3 Deletion Syndrome (Phelan-McDermid Syndrome).

Monteiro P, Feng G.
SHANK proteins: roles at the synapse and in autism spectrum disorder.

Zhou Y, Kaiser T, Monteiro P, Zhang X, Van der Goes MS, Wang D, et al.
Mice with SHANK3 mutations show altered behaviors, synaptic function, and drug responses.

Genetic testing for SHANK3 mutations or deletions is available through multiple diagnostic labs. Chromosomal microarray and sequencing panels are often used to confirm diagnoses such as Phelan-McDermid syndrome or SHANK3-related autism.

• Multiple ongoing trials target SHANK3-related disorders, especially antisense oligonucleotide therapy for conditions like Dravet syndrome.
• SCN1A and SHANK3-related trials

• KCNB1.org – Global community and research updates
• KCNB1 France Association – Family support and advocacy in Europe
• Dravet Syndrome Foundation – Education, research, and family resources
• Phelan-McDermid Syndrome Foundation – Support, awareness, and clinical connections

1. MedlinePlus Genetics – SHANK3 gene
2. GeneReviews – Phelan-McDermid Syndrome Overview