Abstract
BackgroundCerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2–3 years of age. This limits opportunities for early intervention that could otherwise improve long-term outcomes. CP has been recorded in monozygotic twins discordant for the disorder, indicating a potential role of non-genetic factors such as intrauterine infection, hypoxia-ischaemia, haemorrhage and thrombosis. The aim of this exploratory study was to utilise the discordant monozygotic twin model to understand and measure epigenetic changes associated with the development of CP.MethodsWe performed a genome-wide analysis of DNA methylation using the Illumina Infinium Human Methylation 450 BeadChip array with DNA from newborn blood spots of 15 monozygotic twin pairs who later became discordant for CP. Quality control and data preprocessing were undertaken using the minfi R package. Differential methylation analysis was performed using the remove unwanted variation (RUVm) method, taking twin pairing into account in order to identify CP-specific differentially methylated probes (DMPs), and bumphunter was performed to identify differentially methylated regions (DMRs).ResultsWe identified 33 top-ranked DMPs based on a nominal p value cut-off of p < 1 × 10−4 and two DMRs (p < 1 × 10−3) associated with CP. The top-ranked probes related to 25 genes including HNRNPL, RASSF5, CD3D and KALRN involved in immune signalling pathways, in addition to TBC1D24, FBXO9 and VIPR2 previously linked to epileptic encephalopathy. Gene ontology and pathway analysis of top-ranked DMP-associated genes revealed enrichment of inflammatory signalling pathways, regulation of cytokine secretion and regulation of leukocyte-mediated immunity. We also identified two top-ranked DMRs including one on chromosome 6 within the promoter region of LTA gene encoding tumour necrosis factor-beta (TNF-β), an important regulator of inflammation and brain development. The second was within the transcription start site of the LIME1 gene, which plays a key role in inflammatory pathways such as MAPK signalling. CP-specific differential DNA methylation within one of our two top DMRs was validated using an independent platform, MassArray EpiTyper.ConclusionsOurs is the first epigenome-wide association study of CP in disease-discordant monozygotic twin pairs and suggests a potential role for immune dysfunction in this condition.
Highlights
Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity
Subject characteristics The study cohort consisted of 16 CP-discordant twin pairs for which pre-screening suggested a high probability of monozygosity (Table 1)
All were tested for genetic zygosity using data from 65 single nucleotide polymorphism (SNP) from the Infinium arrays
Summary
Cerebral palsy (CP) is a clinical description for a group of motor disorders that are heterogeneous with respect to causes, symptoms and severity. A diagnosis of CP cannot usually be made at birth and in some cases may be delayed until 2–3 years of age. This limits opportunities for early intervention that could otherwise improve longterm outcomes. Cerebral palsy (CP) describes a group of motor impairment syndromes caused by lesions or anomalies of the developing brain [1]. It is non-progressive, but the severity of symptoms may change over time [2]. There are many factors that may be responsible for this increased risk in multiple birth pregnancies, with the most likely being low birth weight and preterm birth, both known risk factors for CP
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