GENETIC INFLUENCES ON DEVELOPMENTAL DISORDERS IN PEDIATRIC POPULATIONS

Abstract

Genetic bases of developmental disorders in paediatric populations are becoming more pronounced; although the extent to which variations in individuals influence clinical severity, neurocognitive outcomes, and comorbidity patterns is still undefined.  This paper has discussed the genetic architecture of common paediatric developmental disorders, such as autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), global developmental delay (GDD), and language impairment and has used a mixed-method approach, which combines whole-exome sequencing (WES), targeted single-nucleotide polymorphism (SNP) genotyping, and clinical phenotype analysis.  Pathogenic or potentially pathogenic variations were identified in 38.4% of the paediatric patients (n=1,200 age 2 to 12 years) and the highest prevalence was found in global developmental delay (52.1%), and autism spectrum disorder (44.7%).  The common high-impact variants were related to the genes that control synaptic signalling (SHANK3, SCN2A), neuronal migration (RELN), chromatin remodelling (CHD8), and metabolism (PAH). Polygenic risk scores, however, showed that common low-effect variants had significant contributions in both ADHD and language disorders.  Quantitative data showed that there were strong correlations between mutation burden and severity of symptoms (r = 0.63, p < 0.001), and increased odds of multisystem comorbidities among children with copy-number changes (OR = 3.24, 95% CI: 2.114.98).  Further, the phenotype-genotype modelling showed that children with mutations of the synaptic pathways had much lower indexes of cognitive performance compared with children with regulatory-region alternatives.  Overall, it was found that both rare high-impact and common polygenic variants have a large influence on the development of children, which demonstrates the importance of both clinical and genomic tests and early initiation of personalised treatments.