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. 2021 Feb 5;23(6):1065–1074. doi: 10.1038/s41436-020-01096-4

Fig. 3. DNA methylation (EpiSign) analysis of peripheral blood from two subjects with variants of unknown clinical significance (VUS) in NSD1, the causative gene for Sotos syndrome type 1.

Fig. 3

The variants are NSD1:c.4982G>C,p.Cys1661Ser) (labeled red and clustering with NSD1 samples) and NSD1:c.3331G>T,p.Asp1111Tyr (labeled red and clustering with control samples). (a) Hierarchical clustering and (b) multidimensional scaling plot of subjects with a confirmed Sotos episignature, controls, and the VUS under investigation. The NSD1:c.4982G>C VUS clustering with the Sotos samples indicates it has a DNA methylation signature similar to that seen in other Sotos samples and suggesting that the variant is pathogenic, while NSD1:c.3331G>T is likely benign. (c) Methylation variant pathogenicity (MVP) score, a multiclass supervised classification system capable of discerning between the 43 different episignatures in EpiSign v2, was applied to the NSD1:c.4982G>C likely pathogenic variant (top) and the NSD1:c.3331G>T likely benign variant (bottom). This classification system generates a probability score for each episignature, with a score near 1 indicating that the sample has an episignature similar to the reference episignature.