DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies

Abstract

Chromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection. Methods: DNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline. Results: The DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively. Conclusion: With the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders.

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report

“…In our patient, it is interesting that the methylation pattern was similar to that of another chromatinopathy caused by a member of the DDB1-Cul E3 ligase complex [ 7 ]. The interpretation of methylation patterns in congenital disorders requires further study.…”

“…The interpretation of methylation patterns in congenital disorders requires further study. The overlap of methylation patterns can be a basis for uncertain or incorrect classifications and that using DNA methylation for disease classifications should be performed with simultaneous consideration of all of the known methylation patterns [ 6 , 7 ]. DNA methylation patterns have the potential to shed light on the molecular mechanisms and assist in the diagnosis of congenital disorders.…”

“…It may be helpful to consider the methylation patterns of other variants within the DDB1-Cul E3 ligase complex for similarities. However, further research is needed to expand our current episignature databases in order to improve the sensitivity of examining methylation patterns [ 6 , 7 ]. Analyzing DNA methylation patterns has the potential to improve our understanding of molecular mechanisms and assist in the diagnosis of congenital disorders.…”

“…Epigenetic chromatin dysregulation is a mechanism in the group of neurodevelopmental disorders known as chromatinopathies. These conditions are caused by the genetic alterations of various components of the epigenetic machinery [ 7 ]. Genetic syndromes often present with overlapping clinical features.…”

Smith-Magenis Syndrome—Clinical Review, Biological Background and Related Disorders

“…Genome-wide methylation episignatures are significant tools to improve the diagnostic process and provide functional clues. The clinical overlap among SMS and the mentioned conditions does not currently find an epigenetic counterpart, as distinctive episignatures have been detected for HDAC4 , MBD5 , MLL1/KMT2A but not for RAI1 [ 123 , 124 ].…”