Abstract

Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.

Highlights

  • Williams syndrome (WS, OMIM 194050), referred to as Williams–Beuren syndrome, is a rare genetic disorder caused by the heterozygous deletion of 26–28 genes at 7q11.23, occurring in ~1 of 10,000 individuals [1]

  • The methylation set was balanced to ensure no significant differences in age and sex between WS patients and controls

  • We could not detect any expression of the ANKRD30B gene in the blood samples from both WS patients and controls

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Summary

Introduction

Williams syndrome (WS, OMIM 194050), referred to as Williams–Beuren syndrome, is a rare genetic disorder caused by the heterozygous deletion of 26–28 genes at 7q11.23, occurring in ~1 of 10,000 individuals [1]. Hypersociability and over-friendliness to strangers, so called “cocktail party” personality, have received considerable attention [1, 2] Such hypersocial behavior seems to be opposite to autism spectrum disorders (ASD), which are characterized by reduced interest in social stimuli and genetic heterogeneity [2]. Several attempts to identify the functions of deleted genes have suggested that GTF2I is implicated in behavioral and/or cognitive abnormalities [3]. This does not explain the phenotypic variability observed among WS patients, and genes related to neuropsychiatric features such as hypersociability remains largely unknown

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