Morphological features in children with autism

Abstract

The central research aim in the present thesis was to extend the insight in several aspects of the role of the morphological features in autism. Clinical morphology might be used as a biomarker for ASD to reveal insight into the complexity of the disorder. In Chapter 1 current terminology and classification in autism and clinical morphology is described and the outline of the thesis is presented. Chapter 2 describes the results of our meta-analysis of reports on the association between ASD and morphological features. The findings of this study indicated a significant association of minor anomalies in autism with a robust pooled effect size (d = 0.84), and thereby provided the strongest evidence to date concerning an association between morphological abnormalities and autism. In Chapter 3 findings are presented of a morphological study on the normal values in healthy schoolchildren. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for morphological features are essential. Therefore, we studied morphological characteristics in a group of 1,007 Caucasian schoolchildren, aged between eight and fourteen, through a body surface examination using detailed definitions for all morphological features. Chapter 4 describes the most comprehensive study to date that assesses morphological features in ASD. This is a study of 421 patients, who underwent a detailed physical examination directed to 683 morphological features. We found that both quantitative and qualitative measurements differed in males vs females. Patients with ASD demonstrate various significant differences from controls in morphological features. This study provided a novel methodology for the identification and validation of biomarkers. In Chapter 5 sensitivity and specificity of these morphological characteristics have been described. We attempted to assess the potential discriminative value of morphological characteristics. We found a strong association between autism and all major and minor abnormalities and common variants, and the whole scale. In addition, we have hypothesized that there is a shared genetic background between ASD and schizophrenia, which requires a follow-up comparison between two disorders. Chapter 6 represented the first case in which autism has been associated with a de novo duplication in 8p21.3 mapped at the molecular level. This relatively small duplication allowed us to identify several gene-dosage sensitive positional candidate genes for his phenotype. Chapter 7 described four patients that implicate microcephalin 1 (MCPH1) in band 8p23.1 as an autism susceptibility gene. Chapter 8 provides a general discussion on findings of the separate studies that we described in this thesis. Morphological features may provide a tool for the further study of the complex interplay between genes and environment. Additionally, these studies might shed some light on genotype-phenotype correlations. In conclusion, recommendations resulting from the studies described in this thesis would include the careful grouping of patients according to their phenotype and types and patterns of in morphological findings, which may be helpful in subsequent molecular studies in search for new genes involved in ASD development.