Autism spectrum disorders (ASDs) delineate a group of behaviorally-defined disorders including autism, PDD-NOS, and Asperger syndrome.
Many efforts are being made to address the clinical heterogeneity of ASDs. At the same time, the diversity of genetic findings in the past decade indicate that ASDs should also be considered genetically heterogeneous 
. This raises the question to what extent the clinical heterogeneity can be explained by the underlying genetic heterogeneity of ASDs. In this study we will address this issue through the assessment of the homogeneity of the ASD phenotype in genetically more homogenous samples.
In addition to the growing number of genetic ASD susceptibility loci with small effect sizes, recent studies have described new “causative” genetic variants in ASDs that are assumed to have a large impact on ASDs 
. They are thought account for about 10–20% of ASD cases 
. These risk variants are likely to show incomplete penetrance and imperfect segregation with disease as most variants have also been observed in non-autistic controls 
. Furthermore, several ASD variants have been shown to cause brain disorders other than ASD, including schizophrenia, mental retardation and epilepsy 
. This combination of incomplete penetrance and pleiotropic phenotypes could indicate that these loci cause a global disruption in brain development, making it more vulnerable to develop a range of different brain disorders. Efforts are required to distinguish distinct aspects of those brain disorders that are caused by these genetic variants with large effect, versus aspects that result from various other (environmental and/or genetic) hits.
A logical starting point would be to assess whether at all, ASD cases ascertained for a particular genetic variant display distinct autistic characteristics. This model can be considered probable when cases carrying the same genetic variant are found to share particular (combinations of) symptoms in higher frequencies than most cases in the idiopathic ASD population. The probability of genetic ASD subphenotypes can be illustrated by Rett syndrome (RTT). A more homogeneous profile of autistic symptoms together with non-autistic symptoms has led to the description of the RTT genetic subphenotype that is formally classified in the DSM-IV-TR as an ASD subtype. RTT is a progressive neurodevelopmental disorder that manifests in girls during early childhood 
. Mutations in MECP2
gene are found in more than 95% of classic RTT cases 
. Patients with RTT appear to develop normally up to 6–18 months of age. Deceleration of head growth is often the presenting symptom. This is often accompanied by general growth retardation, weight loss, and a weak posture and ataxia 
. Social withdrawal and loss of language become apparent at early age. Most patients progressively develop stereotypic hand wringing or washing movements. Other frequent autistic features include expressionless face, hypersensitivity to sound, lack of eye-to-eye contact and unresponsiveness to social cues 
. This illustrates that both specific autistic and non-autistic features characterize RTT. Importantly, the RTT autistic features are also present among the general population of autistic individuals though probably in a much lower frequency.
The modest recurrence of most identified large risk variants so far precludes the inclusion of adequate carrier numbers to evaluate the specificity of the autistic subphenotype per variant. Each of these variants on its own represents only a small proportion (at most 1–2%) of the ASD population 
. Genetic disorders such as RTT that are frequently associated with ASD have associated features such as congenital malformations or somatic disorders that enhance the chance of clinical detection. Therefore, a focus on ASD subjects ascertained for particular a well defined genetic disorder enables the inclusion of larger numbers. Importantly, similar to the newly discovered genetic variants of large effects, most genetic disorders are associated with ASD only in a fraction of affected subjects, thus the defining variants in these disorders also display incomplete penetrance. This warrants a focus on subsets of individuals with a particular genetic disorder that are diagnosed with ASD which could possibly precipitate the impact of a particular variant on autistic symptomatology 
As a proof of concept we studied the ASD phenotype of ASD subjects with 22q11 deletion syndrome (22q11DS) and Klinefelter syndrome (KS, 47 XXY). 22q11DS and KS subjects without
an ASD classification were excluded. 22q11DS and KS are relatively frequent disorders affecting 1–2,000–4,000 and 1–700 respectively 
. Both are clinically defined genetic disorders like RTT and increased rates of ASD have been described in both 22q11DS and KS subjects 
. The presence of both disorders has also previously been described among populations of subjects with ASD 
The structure of the ASD phenotype associated with 22q11DS and KS was compared to a large a large genetically heterogeneous sample of ASD subjects in different statistical analyses involving standard autistic measurements. The analyses aimed to assess differences in symptom homogeneity and the feasibility of differentiation of group-specific ASD-symptom profiles.