Gene panel offers expanded diagnostic capability of inherited retinal diseases

This article was reviewed by J. Fernando Arevalo, MD

The new 248-gene panel provides definitive diagnoses and more personalized care for patients who previously were thought to be negative for an inherited retinal disease (IRD) using a 31-gene panel.

Gene therapy is in its infancy, and it was only in 2017 that a major clinical breakthrough became available with the launch of voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics Inc), which can be used to treat IRDs caused by biallelic mutations in the RPE65 gene.

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“With this therapy and other such therapies on the horizon, it is becoming increasingly important to obtain molecular diagnostics for patients with suspected IRDs,” said Mark Seraly, MD, a resident at the West Virginia University School of Medicine in Morgantown, West Virginia.

Dr. Seraly and associates conducted a retrospective chart review to determine the usefulness of the new 248-gene panel compared with the 31-gene panel for providing molecular diagnoses in 46 patients (50% men; average age, 48 years) from June 1, 2019, to October 31, 2019.

The patients underwent next-generation sequencing with the expanded panel of 248 genes.

Blood or saliva samples were obtained during patient visits. The investigators reviewed the visual acuity, imaging results, electroretinography results, family history, and previous genetic results.

As needed, patients were encouraged to consult a genetic counselor and arrange for variant testing, Seraly said.

Results
Seraly reported that 13 (28.2%) of the 46 patients had positive molecular diagnoses of their IRDs; 12 (26.1%) patients were found to be carriers of pathogenic genes associated with IRDs. These 2 patient groups were urged to undergo additional genetic counseling and variant testing.

Twenty (46.5%) patients had variants of unknown significance, which means that the association between the genetic alterations and the IRDs is not fully understood, he said. Finally, only 1 (2.2%) patient in our cohort had no detected mutations.

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In contrast, 18 (39.1%) patients from this cohort had undergone genetic testing 1 year prior using the 31-gene panel, and the results were negative for an IRD.

“That panel either yielded no identifiable mutations or only those of unknown significance,” Seraly said.

When the same patients underwent retesting with the 248-gene panel, the results differed substantially, with 9 (50%) of individuals gaining new clinically relevant genetic information.

Five patients received an unequivocal molecular diagnosis and the other four were found to be carriers of single pathogenic mutations.

The remaining 9 of 18 were all found to have additional variants of unknown significance, as compared to their prior genetic results, Seraly said.

“The new gene panel provided a wealth of information that facilitated definitive diagnoses for 5 patients with syndromic IRDs,” he said. These diseases included 2 patients with Bardet-Biedl syndrome, 2 with Usher syndrome, and 1 with Cohen syndrome.

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In the same cohort, 4 patients had autosomal-dominant IRDs, and 1 patient had x-linked retinitis pigmentosa. Seraly pointed out, however, that despite these diagnoses, the panel did not include analysis of the RPGR gene, and some patients may have been overlooked.

Three patients in the cohort went on to familial variant testing.

Case presentation
A 10-year-old girl presented with frequent headaches and distorted vision, however, her visual acuity was 20/20 in both eyes. Slit-lamp examination of the anterior chambers was unremarkable.

However, color fundus photos of both eyes showed pale-yellow lesions located inferotemporal and temporal to the macula.

Fluorescein angiography showed that these lesions were hyperfluorescent in the late arteriovenous filling phases. Incomplete retinal vascularization was seen in the temporal peripheral retinas in both eyes.

Optical coherence tomography showed normal macular architecture in the right and left eyes; however, inner retinal folds were visibly associated with an epiretinal membrane in the right eye and an inner retinal tuft in the left eye that was associated with an epiretinal membrane and several small areas of underlying photoreceptor dropout.

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This patient underwent genetic testing and was shown to have a heterozygous mutation in the FZD4 gene on exon 2. Testing of the family showed 4 individuals with similar mutations in the same gene. The patient was diagnosed with autosomal-dominant familial exudative vitreoretinopathy.

“This information allowed us to tailor our follow-up with the patient in clinic and our referral for IRD resources,” Seraly said.

Based on their experience with the 248-gene panel, the investigators concluded that the expanded panel facilitates more personalized patient care—that is, genetic counseling and familial variant testing. The panel also allows refinement of searches for support groups and low-vision resources, and searches for prospective clinical trials in the future.

Seraly concluded that the current study revealed that the majority of patients were only found to harbor variants of unknown significance, indicating that more research is needed to better understand the relationship between a patient’s genotype and the phenotypic expression of their IRDs.

“In addition, in patients who received equivocal results from prior genetic testing, the 248-gene panel provided 50% of patients with new clinically relevant information about their pathogenic mutations,” he said. “More extensive panels may detect larger numbers of IRDs.”

​ Read more by Lynda Charters

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Mark Seraly, MD
e:mpseraly@hsc.wvu.edu
Seraly has no financial interest in this subject matter.