Abstract
Identifying and understanding the genetic contributors to mental health conditions remains a challenge. This is partially due to the complex, polygenic nature of these conditions and the range of underlying genetic variants, including copy number variants (CNV), that contribute to risk. Here we report an individual with severe ADHD who displayed an unusual blood methylome profile, and a strongly positive response during a treatment trial of micronutrients for this condition. The unusual methylome profile prompted a search for structural variants in the genome of this individual, leading to the discovery of two large, rare CNVs, which may help to account for the clinical and epigenetic aspects observed in this case. These CNVs impacted several genes, including RNF4 and EHMT1, both of which encode enzymes involved in DNA methylation, and CACNA1B, which is implicated in neuropsychiatric phenotypes. These CNVs are classified as variants of unknown significance and are likely benign in the clinical setting. Although there is no strong clinical evidence to suggest reclassification of these CNVs, gene regions adjacent to the CNV have been implicated in neuropsychiatric conditions. It seems reasonable to suggest that these rare CNVs may drive the observed perturbation in their methylome profile, and may partially contribute to their ADHD phenotype.