The defining DNA methylation signature of Floating-Harbor Syndrome.

Rebecca L Hood,Laila C Schenkel,Bekim Sadikovic,Guillaume Pare,Peter J Ainsworth,Kym M Boycott,Dennis E Bulman,Sarah M Nikkel

doi:10.1038/srep38803

Abstract

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation “epi-signature” in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.

Highlights

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology
A higher frequency of hypermethylation was observed in individuals with FHS, regardless of genomic location and CpG island proximity (Supplementary Fig. 1)
The cell type estimation showed no significant differences of blood cell composition between FHS patients and controls (Supplementary Fig. 2). Taken together these results indicate that changes in DNA methylation observed in the FHS cohort cannot be attributed to differences in DNA methylation age and/or blood cell type

Summary

Introduction

Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation “epi-signature” in the peripheral blood of individuals with FHS Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Floating-Harbor syndrome (FHS; MIM 136140) is a rare autosomal dominant genetic disorder characterized by short stature, delayed osseous maturation, expressive language impairment, and facial dysmorphology[1,2,3,4]. DNA methylation, the addition of a methyl (CH3) group typically to a cytosine residue within CpG dinucleotides, is the most comprehensively described form of epigenetic modification These epigenetic changes have an essential role in many nuclear functions, and in particular, transcriptional regulation and regulation of chromatin structure. The fine regulation of methylation constitutes an extra layer of control over gene expression

Methods

Results

Conclusion