Neurodevelopmental disorders such as Autism spectrum disorders (ASD), cerebral palsy (CP) and epilepsy are some of the most prevalent neurological disorders and are caused by significant damages to the growth and development of the brain or nervous system. Epigenetic modification, such as DNA methylation, has been implicated as both a mediator and potential biomarker for neurodevelopmental diseases. The complex mechanism of action of neurological diseases poses methodological difficulties. Distinguishing the extent of effect of genetics and environment is confounded by a large number of variables. The study of twins, especially monozygotic (MZ) twins, in which genetics, age, sex, parental factors and shared environment are controlled for, has led to significant advances in our knowledge of disease mechanisms. Molecular studies that evaluate the differences in DNA methylation patterns between disease-discordant MZ co-twins open up the possibility of singling out environmental and stochastic effects that contribute to disease aetiology and may facilitate in biomarker development.

We are studying DNA methylaiton within three MZ twin cohorts discordant for a neurodevelopmental disorder. Specifically, cerebral palsy (CP, 15 pairs), autism spectrum disorder (ASD, 22 pairs) and epilepsy (24 pairs). Genome-wide DNA methylation analysis is being performed using Illumina’s Infinium HumanMethylation450 and the EPIC arrays. Statistical and bioinformatics analysis pipelines are used to analyse methylation data. Gene expression and whole genome sequencing data from the cohorts is also being studied, where applicable, to define the genetic networks associated with each disorder. 
A preliminary analysis of the CP-discordant pairs has been already been performed on DNA from dried blood spots (Guthrie cards) taken at birth. Within-twin pair analysis identified various differentially methylated probes and regions associated gene ontologies such as cell adhesion and inflammation, indicating its significance in CP pathophysiology. This is the first study to access the correlation of epigenomic variations of MZ twins discordant for CP and presents opportunities for future studies of DNA methylation in singletons with CP. Recruitment and methylation analysis using Illumina’s EPIC array for the epilepsy cohort has also been performed.

This project hopes to yield informative and powerful results that have implications for research, advice and treatment options for patients suffering from a broad spectrum of neurodevelopmental disorders. Epigenetic analysis at birth can definitively differentiate the cause and effect and may be able to assist in calculating disease risk before the time of onset. Integrating epigenetic data with that from other ‘omic’ platforms will have the power to further refine models of disease mechanisms and biomarkers.