Rare diseases are defined by the European Union as those which affect less than 5 in 1000 people; yet, cumulatively 30 million people in the UK are affected by a rare disease, or 1 in 17 [
1]. There are over 8000 different type of rare diseases, many of which have ophthalmic impact, and phenotypic heterogeneity means that two in five patients struggle to obtain a diagnosis [
2]. Even where a diagnosis can be obtained, treatment options are often limited [
3]. In the case of common complex ophthalmic conditions, such as diabetic retinopathy, early detection and management can prevent blindness [
4]. Unfortunately, the lack of diagnosis and treatment in several rare ophthalmic conditions results in degeneration of patient vision. Therefore, several research teams worldwide are attempting to improve understanding of rare ophthalmic conditions, with emphasis on improving diagnosis and therapeutic development through genetic analysis, including the UK based 100,000 Genome’s Project [
5], the US-based National Ophthalmic Disease Genotyping and Phenotyping Network (eyeGENE, [
6]) and the Irish Target 5000—Gateway to Vision [
7]. This research has provided a platform for epigenetic analyses, such as the study of differential methylation between rare ophthalmic diseases, which may further facilitate diagnosis and therapeutic research.
Methylation is a reversible post-translational modification to DNA. [
8] Changes in methylation can occur for short or long periods because of heritable, somatic or environmental factors, with the potential to persist over multiple generations. Differential methylation is a key epigenomic biomarker that has been observed in several diseases including several cancers [
9], neurological conditions such as Alzheimer’s disease and Autism Spectrum Disorder [
10], rare renal disorders (Kerr et al., submitted) and several common eye conditions such as age-related macular degeneration [
11] and cataracts [
12]. Therefore, differential methylation may play an important role in characterising rare ophthalmic conditions.
To date, no reviews into differential methylation and rare ophthalmic disease have been conducted. However, several recent studies emphasise the important role methylation may have in ophthalmic development and disease [
13‐
15]. Therefore, there is a need to summarise and critically appraise available evidence, to inform the global debate on what is already known and to evaluate where gaps still exist.