Discontinuities in Autism Spectrum Disorder Traits Among Children with Intellectual Disability

Background:

Intellectual disability (ID) is characterised by significant limitations in cognitive functioning and adaptive behaviour, and is often associated with behavioural and mental health problems at all life stages. IMAGINE ID is a national UK study of up to 10,000 children with ID of known genetic origin that aims to identify genotype-phenotype risk. Whilst ID in general is strongly associated with ASD traits, the distribution of those traits in relation to genetic aetiology is not known.

Objectives:

Our focus is on children with ID due to pathogenic Copy Number Variants (CNV) or Single Nucleotide Variants (SNV), ascertained by NHS Regional Genetics Centres. By means of online/in-person phenotyping, we aimed to assess the prevalence and severity of ASD traits.

Methods:

1027 participants with ID have been phenotyped to date (mean age 9.1 years; SD=3.8, range 4-18 years). Genetic aetiology was established: i) by microarray analyses (NHS accredited laboratories, with array resolutions typically 100kb); ii) aetiological SNV identified from the UK Deciphering Developmental Disorders survey. Phenotyping was by standardized caregiver psychiatric interview, using the Development and Wellbeing Assessment (DAWBA), which has been validated against ADI/ADOS criteria. Ratings of ASD symptoms were made by experienced clinicians, with high reliability. DAWBA ASD symptom counts were used to generate a continuous severity score. A separate Social Aptitude Scale measured aspects of children’s social skills independent of DSM-5 autistic symptomatology.

Results:

42.2% of participants had no significant ASD symptoms, 32.8% of participants met clinical criteria for a diagnosis of ASD, and 25.0% had sub-clinical ASD traits, as measured by a clinical evaluation from interview (DAWBA) material. The ASD group was 63.5% male, the ASD traits group was 52.5% male and the non-ASD group was 46.1% male. There were no significant differences in age, estimated mental age or language age between children with and without clinically identified ASD. When continuous scores were plotted for each subgroup, a normal distribution (confirmed by Shapiro-Wilks analysis) was found for each clinically-defined group. Standardized scores were significantly different (P<0.0001) from one another (ASD clinical: 0.76 (95% CI 0.69 to 0.83), ASD traits: 0.18 (95% CI 0.11 to 0.25), no ASD traits: -0.69 (95% CI -0.77 to -0.62). Social Aptitude Scale (SAS) standardized scores were substantially less discrepant from one another, but the mean SAS score was approximately 2SD below national UK norms.

Conclusions:

IMAGINE ID is the first study systematically to evaluate the prevalence of ASD in a national cohort of children with ID of known genetic origin. Our findings indicate that ID arising from CNV/SNV is strongly associated with markedly impaired social aptitude, independent of whether there coexisted significant ASD traits. This approach has the potential to serve as a new way of examining the heterogeneity within different genetic disorders presenting with the same clinical phenotype. The genotypes in this cohort are currently under investigation.