Abstract
The etiology of cerebral palsy (CP) is complex and remains inadequately understood. Early detection of CP is an important clinical objective as this improves long term outcomes. We performed genome-wide DNA methylation analysis to identify epigenomic predictors of CP in newborns and to investigate disease pathogenesis. Methylation analysis of newborn blood DNA using an Illumina HumanMethylation450K array was performed in 23 CP cases and 21 unaffected controls. There were 230 significantly differentially-methylated CpG loci in 258 genes. Each locus had at least 2.0-fold change in methylation in CP versus controls with a FDR p-value ≤ 0.05. Methylation level for each CpG locus had an area under the receiver operating curve (AUC) ≥ 0.75 for CP detection. Using Artificial Intelligence (AI) platforms/Machine Learning (ML) analysis, CpG methylation levels in a combination of 230 significantly differentially-methylated CpG loci in 258 genes had a 95% sensitivity and 94.4% specificity for newborn prediction of CP. Using pathway analysis, multiple canonical pathways plausibly linked to neuronal function were over-represented. Altered biological processes and functions included: neuromotor damage, malformation of major brain structures, brain growth, neuroprotection, neuronal development and de-differentiation, and cranial sensory neuron development. In conclusion, blood leucocyte epigenetic changes analyzed using AI/ML techniques appeared to accurately predict CP and provided plausible mechanistic information on CP pathogenesis.
Highlights
Cerebral palsy (CP) is a disorder of movement and posture that results from non-progressive injury to the developing brain [1,2]
A total of 230 CpG loci from 258 genes that were found to be statistically significantly differentially-methylated in the CP false detection rate (FDR) p-value < 0.05 compared to controls (Supplementary Table S2)
Apart from coding genes, we identified differentially-methylated CpGs in micro-RNA, open reading frame genes (ORFs), non-coding RNA genes (NCRNAs), small nucleolar RNAs (SNOR), and LOC genes
Summary
Cerebral palsy (CP) is a disorder of movement and posture that results from non-progressive injury to the developing brain [1,2]. The estimated prevalence of CP in the United States population is 3–4 cases per 1000 live births [3]. Cerebral white matter damage results in impaired motor development and control along with increased muscle tone and abnormal reflexes [4]. Associated co-morbidities in CP include attention deficit, disturbed perception and vision, epilepsy, intellectual function [5,6], and Autism Spectrum Disorders (ASD) [7]. Cerebral palsy is more frequently seen in males [8] and among black children compared to white children [9]. Most children diagnosed with CP have the spastic variety [10]
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