Symmetrical Dose-Dependent DNA-Methylation Profiles in Children with Deletion or Duplication of 7q11.23

Abstract

Epigenetic dysfunction has been implicated in a growing list of disorders that include cancer, neurodevelopmental disorders, and neurodegeneration. Williams syndrome (WS) and 7q11.23 duplication syndrome (Dup7) are rare neurodevelopmental disorders with broad phenotypic spectra caused by deletion and duplication, respectively, of a 1.5-Mb region that includes several genes with a role in epigenetic regulation. We have identified striking differences in DNA methylation across the genome between blood cells from children with WS or Dup7 and blood cells from typically developing (TD) children. Notably, regions that were differentially methylated in both WS and Dup7 displayed a significant and symmetrical gene-dose-dependent effect, such that WS typically showed increased and Dup7 showed decreased DNA methylation. Differentially methylated genes were significantly enriched with genes in pathways involved in neurodevelopment, autism spectrum disorder (ASD) candidate genes, and imprinted genes. Using alignment with ENCODE data, we also found the differentially methylated regions to be enriched with CCCTC-binding factor (CTCF) binding sites. These findings suggest that gene(s) within 7q11.23 alter DNA methylation at specific sites across the genome and result in dose-dependent DNA-methylation profiles in WS and Dup7. Given the extent of DNA-methylation changes and the potential impact on CTCF binding and chromatin regulation, epigenetic mechanisms most likely contribute to the complex neurological phenotypes of WS and Dup7. Our findings highlight the importance of DNA methylation in the pathogenesis of WS and Dup7 and provide molecular mechanisms that are potentially shared by WS, Dup7, and ASD.

7q11.23 microduplication syndrome: neurophysiological and neuroradiological insights into a rare chromosomal disorder

“…Because 7q11.23 band harbours different DNA methylation‐controlling genes (like GTF2I and GTF2IRD1 ), it can be speculated that the overexpression of one or more genes of this region causes the methylation‐dependent under‐regulation of other genes involved in brain tissue development (Strong et al . ).…”

Integrative network analysis reveals biological pathways associated with Williams syndrome

“…It has also been reported that disruption of epigenetic regulation is involved in many psychiatric disorders (Geaghan & Cairns, ). Although the epigenetic mechanisms underlying WS are not yet clearly understood, a recent study showed that aberrant DNA methylation occurs not only in the 7q11.23 region but also throughout the genomes of WS patients (Strong et al., ). Thus, epigenetic dysregulation may play a significant role in the upregulation of the three WS‐associated modules (M4, M11, and M12) in this study.…”

Differential Dna Methylation at Birth Associated With Mental Disorder in Individuals With 22Q11.2 Deletion Syndrome

“…[12][13][14][15] The International Consortium on Brain and Behavior in 22q11.2DS has collectively described the prevalence of psychiatric diagnoses in different age groups based on 15 clinical cohorts, reporting a change in prevalence of mental disorders in 22q11.2DS individuals throughout the lifespan. 1 In these clinically ascertained cohorts, one-third of carriers have a below-average intellectual level (IQ, [70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] with adults frequently diagnosed with more severe levels of impairment. [16][17][18] ADHD, particularly the inattentive type, is~10 times more prevalent in children with the deletion, 19 with prevalence estimates ranging from 15.6 to 37% across different studies.…”