Autism Spectrum Disorder (ASD) is a behaviorally defined complex neurodevelopmental disorder. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the core symptoms include qualitative impairments in social communication and the presence of restricted and repetitive behaviors, interests and activities. Though the exact etiology is unknown, recent studies have identified over 100 genes and recurrent genomic imbalances implicated in the etiology of ASD [
1]. Though it seems that the genetic contribution to ASD is complex, accumulating evidence suggests that the risk genes ultimately converge on a relatively small set of molecular pathways, including those critical for synaptic development and plasticity [
2]. One such risk gene is the SH3 and multiple ankyrin repeat domains 3 (
SHANK3) gene [
3‐
5], which lies on the distal long arm of chromosome 22 and whose protein product (by the same name) acts as a scaffolding protein in its interactions with various synaptic molecules, including the N-methyl-D-aspartate receptor (NMDA-R), class I metabotropic glutamate receptors (mGluRs), and the GluR1 a-amino-3-hydroxy-5-methyl–4-isoxazole propionic acid receptor (AMPA-R) [
6]. A recent study reported that a screen for
SHANK3 mutations in 3,833 individuals with ASD and Intellectual disability (ID) revealed a prevalence of a mutation in the
SHANK3 gene in over 2 % of this group [
7]. Estimates of the prevalence of ASD in patients with known abnormalities in the region of the
SHANK3 gene (i.e., patients with 22q13 deletion syndrome or Phelan-McDermid Syndrome (PMS)) are conflicting with published studies reporting anywhere from 0–94 % depending on how the information was obtained [
8‐
10].
Clinical reports of patients with PMS highlight a wide range of systemic and neurologic manifestations, the latter including moderate to profound global developmental delay/intellectual disability, hypotonia, absent or delayed speech, seizures, and decreased perception of pain [
8,
11,
12]. Physical manifestations include minor dysmorphic features, increased incidence of lymphedema, cardiac abnormalities, and renal abnormalities [
8,
11]. Related to the prevalence of ASD in this population, their behavior is described as impaired communication and impaired social interactions with the presence of self-stimulatory behavior [
8].
The aim of this initial study was to systematically characterize the neurobehavioral profile as it relates to symptoms of ASD in patients with PMS and to explore genotype-ASD phenotype correlations. We conducted a standardized interview with 40 parents/guardians of children with PMS ages 3–18 that included the Autism Diagnostic Interview-Revised (ADI-R) [
13] and the Vineland Adaptive Behavior Scale Second Edition (Vineland II) [
14]. Further, in a subgroup of patients, for whom we had access to DNA data, we were able to conduct analyses on the relationship between disruption of
SHANK3 and adjacent genes on specific characteristic symptoms of ASD in PMS. In addition to examining the relationship between
SHANK3 region deletion, we evaluated the potential contribution of the non-deleted copies of 22q13 genes that might carry sequence variants modulating SHANK3 protein’s function. Although
SHANK3 haploinsufficiency, or epigenetic dysregulation of the gene, appears to play a major role in determining the ASD phenotype in PMS, it has been shown that other regions of 22q13 may play a role in the neurobehavioral phenotype of the syndrome [
12,
15,
16]. Thus, it is unclear whether
SHANK3’s loss of function is sufficient for determining ASD or other genes in the region may also play a primary or modifying role. Several of the genes in the
SHANK3 region are appealing candidates because of their demonstrated function:
IB2 encodes a scaffold protein enriched in postsynaptic densities and regulates glutamatergic transmission in the cerebellum [
17], some genes have brain-specific expression patterns (
IB2,
RABL2B), or roles in
SHANK3 regulation (micro-RNA
has-mir124910)
. Based on the previous literature, we hypothesized that the children with PMS would show moderate-profound global developmental delay or intellectual disability and symptoms consistent with the DSM-5 criteria of ASD. It was unclear which symptoms would be more severe or what percent of the sample would meet all of the diagnostic criteria for ASD. Additionally, DSM-5 criteria for ASD requires that that the social communication deficit and other diagnostic impairments must be above what may be expected based on the individual’s intellectual or communication abilities [
18,
19]. Thus, in this population, and others where there is a global developmental delay, it is critical that ASD diagnosis be made in the context of the individual’s general intellectual or communicative skills. Previous studies in our laboratory have similarly aimed to characterize the neurobehavioral profile of ASD in the context of other genetic disorders that often result in both ASD symptoms as well as global developmental delay, namely fragile X syndrome and Down syndrome [
20,
21]. Interestingly, previous studies had indicated that patients with PMS that meet criteria for ASD appear to have smaller deletions restricted only to the
SHANK3 region, while those who did not meet criteria and have a more severe phenotype had larger deletions that also affected other genes [
8,
16]. This may be a result of smaller deletions resulting in less severe global delays and thus more clear demonstration of specific deficits in the social communication domain. Additionally, no data are available about the role of the non-deleted
SHANK3 region genes. Thus, the relationship between
SHANK3 deficit and ASD in PMS appears to be quite complex requiring careful evaluation using standardized, well-validated measures.