Author(s): Jonathan Merritt, Vanderbilt University Medical Center; Jonathan Merritt, PhD, Vanderbilt University Medical Center; Chetan Immanneni, Vanderbilt University; Alan Percy, MD, University of Alabama at Birmingham; Jeffrey Neul, MD, PhD, Vanderbilt Kennedy Center, Vanderbilt University Medical Center //

ABSTRACT: Rett Syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by mutations in the transcriptional regulator Methyl-CpG Binding Protein 2. Although the features of RTT are distinctive, there is variation in clinical severity and clear genotype-phenotype relationships can be observed on a group level. Despite this clear mutation group level genotype-phenotype relationship in RTT, there are individual “outliers” who are either less severely or more severely affected than the specific MECP2 mutation they carry would indicate. One source for this phenotypic variation is the presence of second site genetic modifiers with some genetic variants acting in a protective fashion and others in a detrimental manner to the clinical phenotypes of RTT. In order to identify genetic modifiers of RTT, we performed next generation sequencing on individuals who shared MECP2 mutations but had divergent clinical presentation (“severe” or “mild”). At this time, exome sequences have been obtained for 26 severe and 29 mild individuals, and whole genome sequencing has been performed on 55 severe and 57 mild individuals. To classify candidate modifiers, we performed association testing and pathway analysis to identify genes with differential frequency of variation between these phenotypic extremes. Among top-level results, we found damaging variants in genes related to isoprenoid biosynthesis associate with RTT severity. Understanding the biological role of pathways associated with genetic modifiers in RTT could provide both insight into the pathophysiology of the disorder as well as possible novel therapeutic approaches.

Source of Funding: NIH U54HD061222, NIH P50HD103537, Rett Syndrome Research Trust, International Rett Syndrome Foundation, Vanderbilt Postdoctoral Training Program in Functional Neurogenomics (5T32MH065215)