Our signatures are unique marks that let people know where we’ve been. It turns out that epigenetic modifiers leave their own signatures on the genome. There are between 300-400 proteins that regulate the epigenome, including readers, writers, & erasers of histone marks as well as chromatin remodelers. Genetic variants in the epigenes that encode these proteins cause a variety of rare genetic disorders and studying these conditions can give us unique insight into their function. Nearly all of these disorders are characterized by neurodevelopmental abnormalities and disruption of normal growth. Within each disorder, understanding whether variants of uncertain significance (VUS) in the disorder-associated gene are causative of the patient’s condition is extremely challenging.
The laboratory of Rosanna Weksberg at the SickKids Research Institute (Toronto, Canada) has found that epigene disorders are characterized by gene-specific changes in genome-wide DNA methylation, which represent a unique DNA methylation signature. In a recent study, they investigated Nicolaides-Baraitser syndrome (NCBRS), which is caused by heterozygous missense variants in SMARCA2: the core catalytic component of the chromatin remodeling BAF (SWI/SNF) complex. By utilizing Illumina’s EPIC array they investigated if a DNA methylation signature exists in patients with NCBRS (when compared to controls). Furthermore, they sought to determine if the signature would distinguish the SMARCA2 variants and clinical phenotypes of a cohort of test variants.
Here’s what they found:
- A genome-wide signature of 429 CpG sites
differentiates a discovery set of NCBRS cases from controls
- Many of these CpG map to genes related to neurodevelopmental phenotypes
- A model
built from the differential CpG site methylation classifies VUS in SMARCA2 in
as pathogenic or benign, which matched the patient clinical phenotypes
- Patients with an NCBRS diagnosis and variants in the ATPase/helicase domain are classified as pathogenic, while those outside the domain and without a diagnosis are classified as control
- A unique patient with a VUS distal to the ATPase/helicase
domain in which all NCBRS-associated variants were previously reported was also
analyzed
- This sample had an intermediate model score, with a CpG methylation profile between cases and controls
- The patient had atypically mild NCBRS, especially with respect to intellectual function
- The patient’s methylation at the signature sites was characteristic of controls at neurodevelopmental genes
First author Eric Chater-Diehl shares, “Overall, this work shows that DNA methylation signatures can be domain-specific, and accurately reflect the patient phenotype. This is exemplified by the unique genotype-epigenotype-phenotype correlation of the intermediate patient. The agreement of DNA methylation changes in this patient with a mild neurodevelopmental phenotype suggests that DNA methylation changes in these disorders may be functionally relevant.”
Sign on to DNA methylation signatures as diagnostic tools with functional relevance over at BMC Medical Genomics, July 2019