Contribution of SHANK3 Mutations to Autism Spectrum Disorder

Abstract

Mutations in SHANK3, which encodes a synaptic scaffolding protein, have been described in subjects with an autism spectrum disorder (ASD). To assess the quantitative contribution of SHANK3 to the pathogenesis of autism, we determined the frequency of DNA sequence and copy-number variants in this gene in 400 ASD-affected subjects ascertained in Canada. One de novo mutation and two gene deletions were discovered, indicating a contribution of 0.75% in this cohort. One additional SHANK3 deletion was characterized in two ASD-affected siblings from another collection, which brings the total number of published mutations in unrelated ASD-affected families to seven. The combined data provide support that haploinsufficiency of SHANK3 can cause a monogenic form of autism in sufficient frequency to warrant consideration in clinical diagnostic testing.

Prevalence of SHANK3 variants in patients with different subtypes of autism spectrum disorders

“…Recent studies on Shank3-deficient hippocampal neurons 27,28 and mouse models [29][30][31][32] showed how this gene has an important role in modeling the PSD at the striatum level, regulating basal neurotransmission at the AMPA glutamate receptors, 38 and point mutations. [15][16][17] These results indicate that SHANK3 mutations have a frequency of about 1% in ASD cases, revealing a role for this gene as a possible major contributor in autism. The importance of the proper expression of the SHANK3 gene in ASD is also supported by the finding that 7 out of 28 dysregulated microRNAs in ASD patients target this gene.…”

“…We found five potentially pathogenic alterations (Table 1), resulting in a mutation rate of 2.3%, which is twice as high as the frequency of deleterious SHANK3 mutations reported in previous studies. [15][16][17] In order to exclude intragenic deletion encompassing SHANK3, we performed MLPA analysis of the 22q13 region, but as the kit contains probe for just exons 2, 9, 16, and 20 of SHANK3, there is a possibility that very small copy number variants may have been missed.…”

“…Similar problems have been reported in previous publications. 15,16 Several specific procedures, such as adding dimethyl-sulfoxide 10%, betaine 10%, or using polymerases specific for GC-rich amplicons, proved unsuccessful.…”

“…[11][12][13] Overall, identified genetic causes of autism can be classified as cytogenetically visible chromosomal abnormalities (B5%), copy number variants (10-20%), and single-gene disorders (B5%). 13 Molecular analyses have highlighted the role of point mutations in single genes located in some of these regions: SHANK3 (ProSAP2) on chromosome 22q13, [14][15][16][17] Neuroligin 3 (NLGN3) and Neuroligin 4 (NLGN4) on the X chromosome, 18 Neurexin 1 (NRXN1) on chromosome 2p16, [19][20][21] and Contactin Associated Protein-like 2 (CNTNAP2) on chromosome 7q35. [22][23][24] Notably, both neuroligin and neurexin proteins have key roles in the formation and functioning of synapses, particularly the alignment and activation of glutamate and GABA synapses.…”

“…Some recent studies identified SHANK3 mutations in B1% of ASD cases, 10,[15][16][17] suggesting an important role for this gene in autism pathogenesis. Moreover, recent works in neuronal cell cultures 27,28 and mouse models [29][30][31][32] demonstrated a critical role for this gene in synaptic function, social interaction, and social communication, providing a functional link between SHANK3 deficiency and ASD behavioral features.…”