Genetic testing is proving to be an evolving technology for ophthalmologists.
Diagnosing inherited retinal diseases (IRDs) is not for the faint of heart. Diagnosticians face a number of challenges, according to Ishrat Ahmed, MD, PhD, who discussed this topic recently at the 36th Annual Current Concepts in Ophthalmology conference held at the Johns Hopkins School of Medicine, Baltimore, Maryland. Ahmed is an assistant professor of ophthalmology at the Wilmer Eye Institute in Baltimore.
The challenges inherent in diagnosing IRDs include pleiotropy, which occurs when variants in the same gene cause different retinal disorders; genetic heterogeneity, in which many genes are associated with 1 clinical diagnosis; and the presence of phenocopies, which are variations in phenotype (generally referring to 1 trait) that result from the environment. This may cause confusion when the patient’s phenotype can match a phenotype that is genetically determined.
Testing can provide some clarity, offering a diagnosis and prognosis as well as updating the patient on potential risk to family members. It also can guide management, which may include gene therapy, she explained.
Following diagnosis of, for example, a visual problem, genetic counselors are key figures in the genetic testing process. They provide counseling before and after testing; explain the genetic results, which include discussions of any incidental findings, the molecular diagnosis, and variants of unknown relevance; help the patient with psychosocial adjustment to the diagnosis; and assist with insurance issues.
Next-generation sequencing (NGS) follows the initial counseling, the first tier of which is the targeted gene panel. At this stage, the gene detection rates range from 60% to 70%, with variability based on the type of IRD. This level of testing covers 10 to 500 genes with a high accuracy rate and rapid turnaround, making it the most cost-effective of the tests.
Ahmed discussed 2 gene testing companies, Blueprint Genetics and Invitae, that are involved in genetic analyses. The former covers 351 nuclear genes and the full mitochondrial genome; 16 genes covered by Invitae are not covered by Blueprint Genetics. The company’s benefits include accessibility, reports and analysis, and provider support. In addition to cost, the patient must have an IRD diagnosis.
Invitae covers 329 nuclear genes; the benefits include accessibility and identification of the suspected IRD. A drawback is that more variants of uncertain significance are reported, resulting in more interpretations.
Another company, PreventionGenetics, covers 321 genes. Regarding noncoding variants, which are components of DNA that do not encode protein sequences, Prevention Genetics covers 37 variants, BluePrint Genetics 129 variants, and Invitae 3 variants. Disease-specific panels can be run in the presence of a known family diagnosis or clear phenotype. The number and type of genes are unique to each panel.
NGS techniques include exome sequencing and genome sequencing. These analyses provide a molecular diagnosis in 29% to 67% of previously unresolved cases based on studies.
Exome sequencing covers the entire exome of 20,000 to 25,000 genes, provides good accuracy, and is cost-effective but is associated with a long turnaround. Genome sequencing covers all genes and noncoding DNA but has a high cost and the longest turnaround. Clinicians can consider whole exome sequencing in patients with complex phenotypes with a broad differential diagnosis. The drawbacks include incidental findings and uncharacterized sequence variations in the genome.
This can be undertaken when targeted gene panels are updated to include increased coverage of coding and noncoding variants and inclusion of copy-number variants. Ahmed pointed out that patients can undergo a reevaluation 3 to 5 years after a negative test. Clinicians can offer a reevaluation to patients who have negative or unknown results if the clinical findings are consistent with an IRD, if the IRD had an early onset in childhood to young adulthood, and if there is a positive family history.
There remains plenty of work to do. According to Ahmed, the future will involve addressing disparities in genetic testing detection rates. The inclusion of diverse ethnic backgrounds in the available human genome database should help greatly in that regard.
The Eye2Gene project, an international effort, uses an artificial intelligence algorithm to predict causal IRD genes from multimodal retinal imaging. This advancement aims to facilitate earlier diagnoses, reduce costs, and improve accessibility to genetic diagnoses.
“With the advent of gene therapy, genetic testing has become even more important for our patients. Genetic counselors are crucial members of our IRD team,” Ahmed concluded.