Omics in Ophthalmology: Advances in Genomics and Precision Medicine for Leber Congenital Amaurosis and Age-Related Macular Degeneration

Abstract

Citation: den Hollander AI. Omics in ophthalmology: advances in genomics and precision medicine for Leber congenital amaurosis and age-related macular degeneration. Invest Ophthalmol Vis Sci. 2016;57:1378-1387.The genomic revolution has had a huge impact on our understanding of the genetic defects and disease mechanisms underlying ophthalmic diseases. Two examples are discussed here. The first is Leber congenital amaurosis (LCA), a severe inherited retinal dystrophy leading to severe vision loss in children, and the second is age-related macular degeneration (AMD), the most common cause of vision loss in the elderly. Twenty years ago, the genetic causes of these diseases were unknown. Currently, more than 20 LCA genes have been identified, and genetic testing can now successfully identify the genetic defects in at least 75% of all LCA cases. Genespecific treatments have entered the clinical trial phase for three LCA genes, and for seven LCA genes gene-specific therapies have been tested in model systems. Age-related macular degeneration is a multifactorial disease caused by a combination of genetic and environmental factors. Currently, more than 40 loci have been identified for AMD, accounting for 15%-65% of the total genetic contribution to AMD. Despite the progress that has been made so far, genetic testing is not yet recommended for AMD, but this may change if we move to clinical trials or treatments that are dependent on an individual's genotype. The identification of serum or plasma biomarkers using other ''-omics'' technologies may further improve predictive tests and our understanding of the disease mechanisms of AMD. Ultimately, it is anticipated that predictive tests will help to stratify patients for the most suitable therapy, which will enable the development of precision medicine, tailored to individual needs.

In Vitro Modeling Using Ciliopathy-Patient-Derived Cells Reveals Distinct Cilia Dysfunctions Caused by CEP290 Mutations

“…Mutations in more than 30 genes can cause JSRD phenotypes(Kroes et al, 2016; Suzuki et al, 2016), and at least 20 genes are associated with LCA(den Hollander, 2016; Jacobson et al, 2016). CEP290 mutations can result in multiple divergent phenotypes, including JSRD and LCA.…”

Omics Biomarkers in Ophthalmology

“…Subsequent functional work on the complement system, one of the major pathways predicted from the genetic data, has laid the foundation for ongoing human clinical trials exploring the effect of complement inhibition in AMD. 4,22 Furthermore, strong genetic associations have been identified for PEXG in LOXL1, and for FCD in TCF4. 95,119 Other ocular diseases have not benefited extensively yet from GWAS, possibly due to the large heterogeneity and/or too small sample sizes, emphasizing the need for large consortia and multicenter studies.…”

“…Incorporation of other types of omics data in prediction models for eye diseases has not been done yet on a systems level; however, targeted studies in AMD suggest that there is potential to improve the prediction accuracy by combining genomic and proteomic data. 4, 51,52 Omics research could be valuable in classification of patients in order to predict their response to treatment. For example, since the complement cascade is only one of the affected pathways in AMD, it is possible that patients with alterations in complement regulatory genes would benefit more from complement-inhibiting therapies than others.…”

“…In order to identify rare variants with relatively larger effect sizes, microarrays targeting rare variants (exome chips), whole exome sequencing (WES), or even whole genome sequencing (WGS) is more effective. 4,5 Although WES and WGS have not been used very extensively yet in common eye diseases because of the still relatively high costs, an increase in their use is expected in the upcoming years. Furthermore, relevant information can be extracted by developing and applying algorithms to detect gene-gene and gene-environment interactions.…”

Clinical Role of Epigenetics and Network Analysis in Eye Diseases: A Translational Science Review

“…Acetylation, phosphorylation, and methylation represent some of the most diffuse and important alterations that can occur in tumor onset such as RB [65]. In addition, miRNAs have been demonstrated to play a major role in cancer development [66,67]. Alterations in a large panel of miRNAs, including highly expressed hsa-miR-494, hsa-let-7e, hsa-miR-513a-1, hsa-miR-513a-2, hsa-miR-518c, hsa-miR-129-1, hsa-miR-129-2, hsa-miR-198, hsa-miR-492, hsa-miR-498, hsa-miR-320, hsa-miR-503, and hsa-miR-373, may lead to expression of aberrations of connected genes, thus influencing RB development [23].…”