A Case Control Study to Compare the Phenotype of Children in Lothian with Autism Spectrum Disorder and Either a Sub Microscopic Deletion or Duplication

Special Issue - Genetics of Autism Spectrum Disorder

Austin J Autism & Relat Disabil. 2017; 3(1): 1037.

A Case Control Study to Compare the Phenotype of Children in Lothian with Autism Spectrum Disorder and Either a Sub Microscopic Deletion or Duplication

Fairfield RE* and Clegg SK

Department of Community Child Health’s, University of Edinburgh, UK

*Corresponding author:Rachel Fairfield, Department of Community Child Health’s, University of Edinburgh, UK

Received: February 27, 2017; Accepted: April 12, 2017; Published: April 19, 2017


Introduction: 10% of ASD cases are accounted for by genetic syndromes. There is much interest in susceptibility genes that may contribute to the remaining 90% of “idiopathic” autism. In the last 5 years array CGH has made it possible to identify sub microscopic deletions and duplications. These are either inherited or de novo and have been reported in 10-35 % of ASD cases.

Methodologies: A database of children attending the ASD clinic and the genetics clinic was combined; of these 34 patients met the inclusion criteria of age <18, a diagnosis of ASD and a sub-microscopic deletion or duplication. The genetic diagnosis, its inheritance, the family history, the peri-natal and neonatal history, phenotype and sensory issues were recorded.

Results: The odds ratios for having a deletion increased the chance of maternal bleeding, birth complications, having a lower birth weight, having a learning disability, structural anomalies and dysmorphisms. The odds ratio of a duplication having a family history of ASD was also increased.

Conclusion: Deletions were more likely to be de novo and associated with a more severe phenotype of ASD whereas the duplications were more likely to be inherited and associated with a family history of ASD.

Keywords: Autism spectrum disorder; Genetics; Submicroscopic deletion; Chromosome


ASD: Autism Spectrum Disorder; Array CGH: Chromosome Array Genomic Hybridisation; CNV: Copy Number Variants (CNV); MCHAT: Modified Checklist for Autism in Toddlers; ADI-R: The Autism Diagnostic Interview – Revised (ADI–R)


Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder. It consists of a triad of symptoms that incorporate impairment in social interaction, impaired verbal and non–verbal communication skills and repetitive/stereotyped behaviour [1,2]. ASD has a male predominance and affects around 1% of the childhood population [1].

Due to the high prevalence of ASD all professionals working with young children must be “ASD aware” as early diagnosis and intervention is believed to be advantageous, although this is difficult to prove [3]. When concerns of a possible ASD diagnosis are raised SIGN guidelines recommends use of a specific surveillance tools such as the Modified Checklist for Autism in Toddlers (MCHAT) to identify children at 18 months old that are at risk of ASD however it cannot be used to rule out a diagnosis [4].

To ensure an accurate diagnosis of ASD a multidisciplinary approach is taken. Pediatricians and Speech and Language therapists are among those involved. The Autism Diagnostic Interview – Revised (ADI–R) is a reliable diagnostic tool and ensures a thorough history is taken.

The child is also clinically observed often with the Autism Diagnostic Observation Schedule (ADOS) as the experience of interacting with a child can elicit the clinical evidence of ASD fitting the diagnostic criteria of ICD–10 or DSM-1V [4].

There is great interest surrounding the etiology of ASD. Studies of monozygotic and dizygotic twins have reported that autism is highly heritable [2]. In four studies reviewing the concordance of ASD among twins it was reported that the median value of concordance for both children receiving a diagnosis of ASD was 76% in monozygotic twins in comparison to 0% in dizygotic twins [5].

Approximately 10% of ASD can be explained by a known genetic syndrome. The remaining 90% are known to have “idiopathic autism”. There is a great interest in identifying susceptibility genes. To date 200 have been identified [6]. However, of the genes that have been identified, none are responsible for a large percentage of cases. It has been proposed that multiple genes (with minor effect) together with environmental influences contribute to the heterogeneous neurobehavioral phenotype that is typical of ASD. Karyotype abnormalities found in ASD are associated with dysmorphic features it would be interesting to investigate whether those with “idiopathic” autism in which susceptibility genes have been identified also have associated dysmorphic features [1].

In the last 5 years Chromosome Array Genomic Hybridisation (array CGH) has made it feasible to not only identifies chromosomal abnormalities but also sub-microscopic chromosomal abnormalities. Sub-microscopic alterations or Copy Number Variants (CNV), which are either inherited or de novo, have been reported in 10- 35 % of ASD cases. The most common ASD related CNV’s are the 15q11q13 duplication, the 7q21 duplication and the 16p11.2 microdelection with its reciprocal microduplication [1]. Christian, et al’s paper on sub microscopic genetic abnormalities in ASD reported that duplications were more likely to be inherited and deletions were more likely to be de novo [7].

Gurrieri et al warns that if we do not incorporate the clinical genetics with a critical evaluation of the autism phenotype then the current research into genetics of autism will be in vain [1].

Aims of study

1. In a well-defined population of children who presented to the multi-disciplinary clinics in the Lothian’s with a diagnosis of ASD we will identify those children who have a chromosome microdeletion or micro-duplication.

2. We will identify specific genes with micro-deletions or micro-duplication and so draw correlations between the genetic abnormality, whether it was de-novo or inherited and the phenotype that the child presented with.


We predict that sub-microscopic deletions are more likely to be de-novo and therefore present with a phenotypically more severe ASD whereas the sub-microscopic duplications are more likely to be inherited so we predict that they will have a stronger family history and a phenotypically milder disease.


Study design

Study participants: The following inclusion criteria were used: the patients must be under 18 years old, have a diagnosis of ASD and a genetic diagnosis of either a sub-microscopic deletion or duplication. The children with ASD were diagnosed at a multidisciplinary Communication Clinic in Lothian’s which is run in accordance with the SIGN guidelines on the assessment and diagnosis of ASD [4].

We identified patients by interrogating the Support Needs System (SNS) database for children with a diagnosis of ASD and a chromosomal abnormality. The SNS database is an electronic system that records information about children and young people with additional support needs. Its monitors their progress and ensures access to the appropriate services. It has been implemented in 12 of Scotland’s NHS boards with NHS Lothian having a high level of implementation and utilisation. It is a clinical tool but can also be used for data extraction. A child’s details can only be recorded on the SNS with permission of the parent or guardian.

Community Child Health pediatricians in Edinburgh were also contacted individually to enquire if children who had recently presented to their clinics would fit the inclusion criteria. This identified 89 patients whose notes were assessed according to the inclusion criteria. Of these 6 were excluded as they did not receive a diagnosis of ASD, 43 were excluded because they did not have a genetic diagnosis of a sub-microscopic deletion/duplication and 6 notes did not arrive within the timeframe of data collection. This left 34 patients who were included. One patient had a deletion and duplication so was included under both headings thus giving 35 data sets for analysis.

Data collection

A comprehensive clinical description of each child was recorded in a spreadsheet detailing the child’s phenotype. See Appendix 1.

The antenatal history including whether drugs and alcohol were taken during pregnancy, if the mother experienced depression, infection or bleeding during pregnancy and the parental age at birth were recorded as these have been shown to be pre-natal factors with the strongest evidence for an association with autism risk [8]. The birth history was recorded including whether the child was pre-term (<34 weeks) or term (>34 weeks), the birth weight (kg) and birth trauma were recorded as prematurity, low birth weight and birth trauma have been reported to be autism risk factors [8]. Higher rates of CNV’s have been found in individuals with co- existing structural anomalies and dysmorphisms [9] so these will be documented. The patient’s weight, height and head circumference will be recorded in centiles at the time of diagnosis as it has been reported that macrocephaly (>97th centile) and increased height and weight is found in ASD [10,11]. A history of developmental regression, a diagnosis of a learning disability and epilepsy will also be recorded as these are frequently reported in ASD [4]. A family history of ASD, learning difficulties and a psychotic illness will be recorded as recommended by SIGN guidelines [4]. The child’s sensory behaviors will be recorded as these are included in the general warning signs of ASD [4].

Genetics collection

Blood samples that have previously been obtained from all the children have undergone molecular genetic studies including DNA extraction and array CGH screening for sub-microscopic deletions/ duplications. Some genetic data was missing from the files so the genetics department was contacted to provide the genetic test results of 7/34 children and the parental genetics for 12/34 children.


The 34 patients that were included comprised of 71% males and 29% female. The study included 63% deletions and 37% duplications. Chi-square test of association investigated if there was a statistically significant (p<0.05) association between having a deletion or duplication and the risk factors for ASD that were recorded in the spreadsheet. Odds ratios were also calculated.

Duplications were four times more likely to be inherited and deletions were more likely to be de novo however this was not statistically significant p=0.17 odds ratio= 4.44 95% CI (0.62-32.41) (Figure 1.0).