Because the clinical data are not complete in most cases,

it is difficult to draw firm conclusions about the relationship between specific SHANK3 variants and clinical features related to ASD. This challenge is best illustrated in three cases with very similar mutations (p.A1227fs, p.E1311fs, and p.R1117X) in exon 21 encoding the proline-rich Homer binding site of SHANK3 ( Figure 1A). Mutations p.A1227fs and p.E1331fs were found in patients with ASD or PDD-NOS, severe language delay, and significant intellectual disability ( Boccuto et al., 2013; Durand et al., 2007), while p.R1117X was found in patients with schizophrenia and mild intellectual disability ( Gauthier et al., 2010). Similarly, in other cases with almost identical small microdeletions (<100 kb) including SHANK3, neurobehavioral phenotypes were quite variable ( Boccuto et al., 2013; Bonaglia et al., 2011; Dhar et al., BIBW2992 ic50 2010). One hypothesis to explain these Perifosine differences is the presence of a genetic or epigenetic variant in the other allele of SHANK3, or haploinsufficiency and positional effects of deletions on other genes known to cause autosomal-recessive neurological disorders in the 22q13.3 region. For example, genes implicated in metachromatic leukodystrophy (ARSA), congenital disorders of glycosylation

(ALG12), and spinocerebellar ataxia type 10 (ATXN10) are mapped within the 22q13.3 region. In addition, mutations

or allelic variation in as-yet-unidentified genes that function as epistatic modifiers for SHANK3 could influence the phenotypes associated with SHANK3 defects. In the cases of SHANK1 and SHANK2 mutations associated with ASD, no studies relating genotype and phenotype have been reported. The penetrance of SHANK2 mutations in ASD is not complete in some cases ( Leblond et al., 2012). This observation has led to the proposal of a multiple hit model to explain the clinical relevance of SHANK2 mutations. Because the number of ASD cases with two genetic hits including next SHANK2 is small, the validity of the model remains to be tested in additional patient cohorts or by functional studies. Interestingly, microdeletion of SHANK1 is only penetrant in males with mild ASD in families studied ( Sato et al., 2012). The molecular basis for gender-specific penetrance related to SHANK1 mutations is not immediately clear but may provide an opportunity to investigate mechanisms underlying higher male gender-specific risk in ASD. Deletions involving entire SHANK family genes in ASD predict that haploinsufficiency is the primary mechanism underlying ASD pathogenesis ( Wilson et al., 2003). By comparison, for point mutations such as missense mutation and small intragenic deletions identified in SHANK2 and SHANK3, the pathogenic mechanism is less clear ( Bonaglia et al., 2011; Durand et al., 2012; Moessner et al., 2007).