Genetic testing for inherited retinal degenerations: Triumphs and tribulations

Abstract

Inherited retinal degenerations (IRDs) are a genotypically and phenotypically diverse group of conditions. Great strides have been made toward identifying the genetic basis for these conditions over the last 30 years-more than 270 different genes involved in syndromic and nonsyndromic forms of retinal dystrophies have now been identified. The identification of these genes and the improvement of clinical laboratory techniques have led to the identification of the genetic basis of disease in 56-76% of patients with IRDs through next generation sequencing and copy number variant analysis. Genetic testing is an essential part of clinical care for patients affected with IRDs and is required to confirm the diagnosis, understand the inheritance of the condition, and determine eligibility for gene-specific treatments or clinical trials. Despite the success achieved in determining the genetic cause of these conditions, several challenges remain, which must be considered when providing genetic testing and genetic counseling to patients. For this reason, an integrated team of ophthalmic and genetic clinicians who are familiar with these challenges is necessary to provide optimal comprehensive care to these patients.

Syndromic Inherited Retinal Diseases: Genetic, Clinical and Diagnostic Aspects

“…Currently, the most efficient approach for genetic diagnosis in monogenic diseases, including IRDs, is next-generation sequencing (NGS). NGS technologies facilitate the screening of the entire genome (whole genome sequencing, WGS); of all protein-coding regions (whole exome sequencing, WES); or of protein-coding regions of pre-determined panels of genes (targeted NGS, T-NGS) [79,80]. Since protein-coding regions comprise only 1-2% of the entire genome while harboring over 85% of variants causing Mendelian disorders, WES is still considered as the method of choice for genetic analysis, in both clinical and research settings.…”

Genetic Testing of Inherited Retinal Disease in Australian Private Tertiary Ophthalmology Practice

“… 43 Clinicians may be unaware which patients are suitable candidates, the appropriate test to order, how to interpret results, or the associated cost of genetic testing. 21 , 43 Further education may be required to educate clinicians and patients regarding the benefits of genetic testing using informative resources such as the Retina International Campaign, “Know Your Code” ( www.kyc.retinaint.org ). 44 Confoundingly, there is also variation in testing guidelines between international and Australian guidelines, with international patient advocacy groups such as Retina International detailing a need for global consensus in published guidelines.…”

“… 14 , 17–19 The success of genetic testing in identifying the disease-causing variant varies depending on patients’ specific diagnosis, 17 age, 20 and whether the responsible gene and/or pathogenic variant has been previously identified in IRD patients and/or family members. 21 New developments in testing methodology and gene therapy have further highlighted the important role of genetic testing for IRDs.…”

New Omics—Derived Perspectives on Retinal Dystrophies: Could Ion Channels-Encoding or Related Genes Act as Modifier of Pathological Phenotype?

“…Mutations in a specific gene can give rise to distinct IRD phenotypes of variable severity, progression and mode of inheritance. As a consequence, establishing a reliable genotype-phenotype relationship is rarely possible [15]. Causative genes are involved in most of molecular mechanisms related to retinal function, among which the most recently associated is the synaptic activity of retinal cells mediated by different ion channels.…”