SHANK3 – Autism Spectrum Disorder

SHANK3 encodes a postsynaptic scaffolding protein essential for excitatory synapse structure and function. Heterozygous loss-of-function variants in SHANK3 cause autosomal dominant neurodevelopmental disorders featuring moderate to profound intellectual disability and autism spectrum disorder (Autism Spectrum Disorder). Clinical presentations often include severe speech delay, cognitive regression around 3 years, hypotonia, and epilepsy. Haploinsufficiency of SHANK3 is a well-recognized monogenic cause of ASD, supporting its inclusion in diagnostic gene panels for early molecular diagnosis and genetic counselling.

Multiple independent case series report de novo and inherited heterozygous SHANK3 deletions and truncating mutations in autism. Autosomal dominant inheritance is the predominant mode, with segregation documented in sibships including 2 affected relatives in multiplex families (PMID:25646853). Over 100 unrelated ASD probands have been described with de novo or truncating SHANK3 variants (PMID:25188300), consistent with a monogenic etiology. Case-control studies estimate SHANK3 disruption in up to 1% of ASD cohorts, with recurrent variants such as c.3679dup (p.Ala1227GlyfsTer69) observed in 18 individuals from 16 families (PMID:34737294).

The SHANK3 variant spectrum encompasses large 22q13.3 deletions, frameshift and nonsense mutations, splice-site changes, and rare missense alleles. At least 40 distinct truncating variants and over 10 missense changes have been reported in ASD, with functional studies focusing on the ankyrin and sterile alpha motif domains. One representative variant, c.3259_3259delC (p.Ser1088ProfsTer6), disrupts exon 21, leads to premature termination, and segregates with ASD and epilepsy (PMID:25646853). These deleterious variants reduce synaptic SHANK3 levels, confirming haploinsufficiency as the pathogenic mechanism.

Animal and cellular models demonstrate convergent synaptic dysfunction. Shank3-deficient mice exhibit reduced dendritic spine density, impaired long-term potentiation, and altered dendritic arborization, mirroring human cellular assays (PMID:21606927). In vitro, ASD-associated SHANK3 stop mutations accumulate in neuronal nuclei or disrupt postsynaptic targeting, leading to fewer excitatory synapses without affecting inhibitory contacts (PMID:26045941).

Electrophysiological studies reveal specific deficits in metabotropic and hyperpolarization-activated currents. ASD-associated SHANK3 mutations impair mGluR-dependent long-term depression in hippocampal neurons (PMID:30868621) and cause Ih channelopathy in human and mouse neurons through disrupted HCN channel scaffolding (PMID:26966193). Pharmacological interventions, including oxytocin administration, rescue social memory and attention deficits in Shank3 mutant rats, underscoring therapeutic potential (PMID:28139198).

While rare SNP association studies in Chinese cohorts found no common risk alleles in SHANK3 regulatory regions (PMID:23468870), the overwhelming evidence from de novo truncating variants and functional concordance supports a Definitive gene-disease relationship. SHANK3 testing should be prioritized in ASD diagnostics, and molecular insights into synaptic modulation offer avenues for targeted therapies. Key Take-home: SHANK3 haploinsufficiency underlies a highly penetrant, clinically actionable synaptopathy in ASD.

References

• PLoS genetics • 2014 • Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PMID:25188300
• PLOS ONE • 2015 • Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder. PMID:25646853
• Molecular psychiatry • 2012 • SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. PMID:21606927
• Molecular autism • 2015 • Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. PMID:26045941
• Synapse (New York, N.Y.) • 2019 • Autism-associated Shank3 mutations alter mGluR expression and mGluR-dependent but not NMDA receptor-dependent long-term depression. PMID:30868621
• Science • 2016 • Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. PMID:26966193
• eLife • 2017 • Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. PMID:28139198
• NPJ genomic medicine • 2021 • A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder. PMID:34737294
• PLOS ONE • 2013 • Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PMID:23468870

Evidence Based Scoring (AI generated)