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  • The Dutch Central Committee on Research Involving Human Subjects had approved the research protocol. Patient associations and centers for clinical genetics, and pediatrics were involved in recruiting the children for the original psychiatric surveys out of which the subjects for the present study were selected (see below). A newsletter presented on the web or in writing, had informed parents and children of the aim and methods of the study. Parents and children of had to apply actively for participation in the study by contacting the research team. Subsequently they were sent written information about the selection criteria and the implications of participation in the study. They were invited for assessment if they met the inclusion criteria. Written informed consent was obtained from participants (if older than 12 years of age) and their parents or guardians according to the declaration of Helsinki. 22q11DS or KS subjects were selected for this study if they had been diagnosed with an ASD via previous surveys on general psychopathology on children with 22q11DS (n = 90) and Klinefelter Syndrome (KS) sample (n = 51), all 47, XXY none higher aneuploidies, no mosaics). (See [16], [17] for more extensive details on recruitment and further characteristics of the patient samples). This survey had resulted in an ASD classification in 14 of the 51 KS boys (14/51 = 27%) and 39 of the 90 22q11DS children (39/90 = 43%). The classification of an autism spectrum disorder (ASD) was made on the basis of DSM-IV-TR standardized interviews and the Autism Diagnostic Interview (ADI-R) [24]. Videotapes of all subjects and the DSM-IV-TR/ADI-R outcomes were discussed in a consensus meeting headed by the head of the department. The consensus meeting served to control for procedural mistakes and to verify whether the classifications through the DSM-IV-TR and ADI-R interviews were in agreement with the clinical judgment. All 22q11DS and KS subjects with an ASD met ADI-R thresholds and DSM-IV-TR criteria. A genetically heterogeneous ASD sample was recruited as part of a genetic study of autism and from a clinical sample of patients referred to the department of child and adolescent psychiatry for diagnostic reasons. Thus, these subjects were unascertained for their genotype and should therefore represent a reference sample of maximal genetic heterogeneity. Inclusion criteria were: age four years or older, no severe medical or neurological illness, IQ>40. The final sample consisted of 372 verbal subjects. Study participants ranged in age from 4 to 20 years. Similar to the ASD cases obtained from the 22q11 and XXYDS cohorts, all subjects out of the heterogeneous ASD sample had been evaluated in consensus meetings to confirm ASD diagnosis through the interviews and all subjects met ADI-R thresholds. IQ had been assessed by means of the Dutch versions of the Wechsler scales (WPSSI WISC III and WAIS) [25]–[27] in the KS and 22q11DS sample and in a significant part of the ASD heterogeneous group (65%). IQ scores of the heterogeneous ASD sample that could not be assessed with the Wechsler scales have been assessed with the RAVEN Progressive Matrices [28] the Mullen Scales of Early Learning [29] or the Snijders-Oomen non-verbal intelligence test-Revised [30]. No difference in intelligence level between those with and those without ASDs had been found in both the 22q11DS and KS samples in the original psychiatric surveys (see [16], [17]). ADI-R subscale and symptom variables were entered in the statistical analyses for phenotype comparisons. The ADI–R is an established ‘gold standard’ in diagnostic/phenotypic evaluations of autism. It is an extensive clinical interview administered to the parents. The interview focuses on the three core or so called “content” domains of autism (i.e. qualitative abnormalities in social interaction (S), qualitative abnormalities in communication (C) and stereotyped and repetitive behaviors (R) [24]. ADI-R items are coded for these domains and also for an “age of onset” domain. A classification of an autism spectrum disorder is applied when scores in all domains are met or when scores are met in two core domains and meet criteria on the “age of onset” domain, but are one point away from meeting autism criteria in the remaining core domain. Reliability of the ADI-R in a population with mild to moderate mental retardation has been established [31]. The ADI-R may also be used to assess profiles of autistic symptomatology [32], [33]. The ADI–R algorithm is composed of 37 symptom “items”. These items were originally selected as a minimum for optimal ASD classification [24]. ADI-R labels consist of 2 to 5 items and are directly related to the DSM-IV-TR criteria of an Autistic Disorder. As a result, 12 ADI-R labels are used. Each ADI-R domain consists of 4 labels, eg S1-4, C1-4 and R1-4. Items are coded as 0 (ASD behavioural symptom specified not present), 1 (specified behaviour not sufficient to code “2”) or 2 (specified ASD symptom present). Maximum label scores thus range from 4–10. An overview of the description of the ADI-R items, labels and the ADI-R domains of the algorithm is provided in Tables S1 and S2. Symptom homogeneity was operationalized as the (inverse of the) mean number of ADI-R algorithm items within each ASD group on which the subjects scored clearly in the autistic range, i.e. ADI-R item score  = 2. Thus, per subject, the number of items with score  = 2 were counted. A lower number of ADI-R items that reached the autism criterion can be considered indicative of a relative reduction in symptom heterogeneity. Differences between groups in number of ADI-R items on which the autism criterion was reached were analyzed by means of a univariate analysis of variance, with post hoc Bonferroni multiple comparisons. Discriminant analyses (DA) were performed to determine whether the genetic disorder ASD subsamples could be differentiated from the heterogeneous ASD sample on the basis of ADI-R variables. The analyses addressed the question to what extent ADI-R label and/or ADI-R symptom item profiles could successfully discriminate 22q11DS or KS ASD profiles from the heterogeneous ASD sample profile (i.e., 22q11DS+ASD vs. heterogeneous ASD, and KS+ASD vs. heterogeneous ASD). In addition, three group DAs were performed to explore the separation of the three groups by means of 2 discriminant functions. For all discriminant analyses, stepwise Wilks' lambda was used, with probability of F for entry and removal of variables set at 0.5 and 0.10 respectively. For classification the within-group covariance matrices were used and prior probability was set to equal for all groups.
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