Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments

Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. 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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…CNVs and truncating mutations of SHANKs have been identified in almost 1% of ASD patients 185 , making the SHANK family of proteins central to the pathophysiology of autism.…”

Phelan–McDermid Syndrome and SHANK3: Implications for Treatment

“…A review of recent studies in ASD using CMA or sequencing suggests that at least 0.5 % of ASD can be explained by deletions (0.16 %) or mutations (0.31 %) in SHANK3 [37]. In addition, up to 2 % of ASD with moderate-to-profound ID can be explained by loss of SHANK3 [38,39]. Men and women appear to be equally affected by PMS [40].…”

“…Soorya et al [10] used standardized methods to evaluate for ASD, which includes the Autism Diagnostic Interview-Revised [47], Autism Diagnostic Observation Schedule-G [48], and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria [49], and found that 84 % of the patients with PMS in their study met the criteria for ASD. Patients with PMS are also commonly affected by ID, with approximately 75 % of patients showing severe-to-profound intellectual deficits [10,11,38,50].…”

Deficiency of Shank2 causes mania-like behavior that responds to mood stabilizers

“…Early genetic studies implicated SHANK family genes in both autism spectrum disorders (ASDs) and intellectual disability (3)(4)(5)(6). Increasing evidence supports a role for SHANK family genes in a broad spectrum of neuropsychiatric disorders (7).…”