Deciphering the role of epigenetics in self-limited epilepsy with centrotemporal spikes
Introduction
Self-limited epilepsy with centrotemporal spikes (SECTS), previously termed benign rolandic epilepsy, is an age-dependent focal epilepsy of childhood. Onset is usually between 5 and 10 years of age and characterized by unilateral sensorimotor seizures, normal neurological development and the electroencephalogram (EEG) trait of centrotemporal spikes.
Historically, SECTS was thought to be caused by genetic factors (Bray and Wiser, 1965; Heijbel et al., 1975). A purely genetic basis for SECTS has been challenged over the years by the paucity of affected relatives and lack of concordance in monozygotic (MZ) twins (Vadlamudi et al., 2004, 2006).
To date, genes such as GRIN2A, DEPDC5, ELP4, BDNF and KCNQ2 have been implicated in SECTS. For a number of these genes the data is not strong or the observations are in cases on the severe end of the phenotypic spectrum of focal epilepsies, often with associated neurological impairment (Xiong and Zhou, 2017).
The role of environmental factors needs consideration in SECTS, potentially mediated by epigenetic mechanisms such as DNA methylation. Recently, epigenetic analyses of MZ twins discordant for neurodevelopmental disorders such as cerebral palsy (Mohandas et al., 2018) have identified differences in DNA methylation in relevant genes. Whilst epigenetic states have a significant tissue-specific component, recent evidence has shown that for some brain disorders including epilepsies, epigenetic analyses of peripheral tissues are of value (Karsten et al., 2011; Yuen et al., 2018).
DNA methylation analysis of Guthrie cards (heel-prick test cards routinely taken shortly after birth) enables identification of epigenetic marks that occur prior to the disease onset supporting the mark being a potential cause rather than effect of the disease, an inference further supported if the mark persists after disease onset.
In this pilot study, we analysed genome-wide DNA methylation in three pairs of MZ twins discordant for SECTS. Our primary aim was to identify gene regions that show SECTS-specific differences in DNA methylation across all pairs at birth and further observe if any of these or other differences was present post diagnosis.
Section snippets
Study participants
Ethics approval was obtained from the Mater Health Services (ethics approval number HREC/13/MHS/114). SECTS-discordant MZ twin pairs were recruited through Twins Research Australia (https://www.twins.org.au) and the Epilepsy Research Centre Database (http://www.epilepsyresearch.org.au). Zygosity testing confirmed monozygosity. Informed consent was obtained from each twin individual. Diagnoses were confirmed with clinical and EEG findings. Blood spots from stored neonatal Guthrie cards were
DNA methylation differences at birth
Data exploration using principal component analysis and multi-dimensional scaling was performed to estimate the sources of variation in the data. Known covariates including age, sex, birth weight, birth order, medication and gestational age were tested to capture similarities and variations between data samples. DMPs were identified but none were considered statistically significant, as they were not within the false discovery rate threshold of 0.1.
To minimise type 1 errors, we focussed on
Discussion
The genetic architecture of SECTS is complex and is likely to involve an interplay between genes and environment, in part mediated by epigenetics. Whilst no gene regions reached our stringent threshold for significance in our limited discordant twin sample, the potential role of epigenetics is supported by the observation that many of the identified genes have been previously reported in epilepsies and also have large effect sizes.
The LYPD8 gene was associated with a top-ranked DMR at birth and
Conclusions
Although limited by small numbers, we have demonstrated the novel utility of the longitudinal, discordant MZ twin model, to facilitate a deeper appreciation of the complex neurobiology of SECTS.
Ethics approval and consent to participate
Informed consent was obtained from each twin individual. A multi-centre ethics approval was obtained with the lead site being Mater Health Services (ethics approval number HREC/13/MHS/114).
Availability of data
The datasets used and/or analysed during the current study are available from the corresponding author on request.
Declaration of Competing Interest
The authors declare that they have no competing interests.
Funding
This work was supported by grant from the Financial Markets Foundation for Children (grant number 2013-207). LV was supported by a Queensland Health Research Fellowship. This work was also supported by The University of Queensland Mayne Bequest Funds, Royal Brisbane and Women’s Foundation Grant, Viertal-Charitable Foundation, Ramaciotti Establishment Grant and The Servier Barry Young Fellowship in Neurology.
Acknowledgements
The authors thank the participants and their families. The authors are also grateful for the support from the Murdoch Children’s Research Institute (MCRI), which is supported in part by the Victorian Government’s Operational Infrastructure Support Program.
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