Sometimes the only way to tell who’s who is with their signatures. It turns out that epigenetic signatures can tell one disorder from another, and even help find new ones. Chromatin remodelers play important roles in neurodevelopmental disorders (NDDs). Pathogenic genetic variants in many of these genes cause specific NDDs. These are often associated with unique DNA methylation signatures, consistent patterns of differential DNA methylation that distinguish the disorder from controls and often related disorders. One of these remodelers is SRCAP, an ATPase that incorporates the histone variant H2A.Z into nucleosomes. Truncating variants in last two exons of SRCAP cause Floating-Harbor syndrome (FLHS), a neurodevelopmental disorder characterized by typical craniofacial features, speech and language delay, and short stature. FLHS is also associated with a specific DNA methylation signature. While variants in the last two exons have been well studied, the association of those in the remainder of the gene with disease was unknown.
The laboratories of Rosanna Weksberg (SickKids, Canada) and David Koolen (Radboud University, The Netherlands) investigated the epigenetic and phenotypic consequences of truncating variants in SRCAP outside the FLHS locus. They collected a cohort of 33 individuals with developmental delay having these variants, 28 with variants proximal to the FLHS locus, 5 with variants distal to it. They hypothesized that these individuals had an undescribed NDD, and sought to demonstrate this using DNA methylation with the Illumina EPIC array. Overlap with the FLHS signature would indicate the same condition while a new/unique DNA methylation signature would suggest a distinct disorder. Here’s what they found:
- Phenotypically, individuals with proximal and distal variants were distinct from FLHS, lacking the FLHS-specific facial features and short stature, while often having behavioral and psychiatric problems and musculoskeletal issues
- The authors first defined an FLHS signature (464 CpG sites) comparing blood DNA from individuals with FLHS to controls
- At these FLHS CpGs, the proximal and some distal cases clustered intermediately between FLHS and controls, suggesting an overlapping but distinct disorder
- Next, they identified a proximal SRCAP DNA methylation signature of 347 CpG sites by comparing proximal SRCAP samples to controls
- There were 77 CpG sites shared between the two signatures
- Finally they developed machine learning classification models based on each signature
- Each model (proximal and FLHS) classified validation cases positively, while classifying the other group negatively, suggesting that these represent two distinct disorders
- While all distal cases were negative on the FLHS signature, some were positive on the proximal signature while others were negative, suggesting different mechanism at work
Co-lead author Eric Chater-Diehl shares “This study shows how useful epigenetic methods can be in clinical applications. While the clinical phenotype of the individuals with the proximal and distal SRCAP variants are different than FLHS, they is also a lot of inter-individual variation. In this and other emerging disorders, this means the historical standard of shared typical phenotypic features cannot be used as the main evidence to define a novel syndrome. We show that DNA methylation can provide much more information in these cases, here helping us define this condition and distinguish it from FLHS.”
Check out the full story in the American Journal of Human Genetics, April 2021