Rare diseases of epigenetic origin: Challenges and opportunities

Abstract

Rare diseases (RDs), more than 80% of which have a genetic origin, collectively affect approximately 350 million people worldwide. Progress in next-generation sequencing technology has both greatly accelerated the pace of discovery of novel RDs and provided more accurate means for their diagnosis. RDs that are driven by altered epigenetic regulation with an underlying genetic basis are referred to as rare diseases of epigenetic origin (RDEOs). These diseases pose unique challenges in research, as they often show complex genetic and clinical heterogeneity arising from unknown gene-disease mechanisms. Furthermore, multiple other factors, including cell type and developmental time point, can confound attempts to deconvolute the pathophysiology of these disorders. These challenges are further exacerbated by factors that contribute to epigenetic variability and the difficulty of collecting sufficient participant numbers in human studies. However, new molecular and bioinformatics techniques will provide insight into how these disorders manifest over time. This review highlights recent studies addressing these challenges with innovative solutions. Further research will elucidate the mechanisms of action underlying unique RDEOs and facilitate the discovery of treatments and diagnostic biomarkers for screening, thereby improving health trajectories and clinical outcomes of affected patients.

Keywords: DNA methylation; bioinformatics analysis; chromatin remodeler; epigenetics; histone modification; rare disease.

FIGURE 1

Schematic of Epigenetic Regulatory Mechanisms Associated With RDEOs: Chromatin Remodelers, Histone Modifications, and DNA Methylation. Abbreviations: ac, acetylation; me, methylation.

FIGURE 2

Challenges (left panel) and opportunities (right panel) in RDEO research. (A) Technical challenges include small sample size and low statistical power, cell type heterogeneity, and specificities of developmental time points. Example solutions include a reference epigenome, single-cell epigenomic profiling, and relevant RDEO models, such as animal models, primary samples, iPSCs, and organoids. (B) RDEOs often present with complex disease–phenotype relations, as the variants driving the RDEOs can drive widespread epigenetic dysregulation. Approaches such as RNA-Seq and EWAS can help to identify affected downstream elements and allow investigation of the mechanisms underlying the RDEO phenotype. (C) RDEOs commonly present with genetic and phenotypic heterogeneity. As an example of RDEO genetic heterogeneity, PRC2-related overgrowth syndromes are a group of RDEOs with a similar clinical phenotype all of which are linked to variants in PRC2. In contrast, patients with the same RDEO and variants in the same gene can have a range of clinical symptoms. Studies of interacting proteins in the same pathway can help to delineate the complexity of genetic heterogeneity, and tools such as the epigenetic clock may be applied to evaluate or monitor phenotypic heterogeneity. Abbreviations: CpGs, cytosine-guanine dinucleotides; DNAm, DNA methylation; RDEO, rare disease of epigenetic origin; EWAS, epigenome-wide association study; iPSC, induced pluripotent stem cell; PRC2, Polycomb repressive complex 2; RNA-Seq, RNA sequencing.