Predictive value of genetic testing for inherited retinal diseases in patients with suspected atypical autoimmune retinopathy

Abstract

Purpose: The clinical features of autoimmune retinopathy (AIR) can resemble and be difficult to differentiate from inherited retinal degenerations (IRDs). Misdiagnosis of an IRD as AIR causes unnecessary treatment with immunosuppressive agents. The purpose of this study is to calculate the predictive value of genetic testing for IRDs in patients with suspected AIR and provide clinical examples where genetic testing has been useful.

Methods: We identified patients seen at MEEI between April 2013 and January 2017 for whom the differentiation of AIR vs. IRDs was difficult based on clinical assessment alone. All patients had some atypical features for AIR, but tested positive for anti-retinal antibodies. Within this group, we identified six patients who had genetic testing for IRDs with the Genetic Eye Disease panel for retinal genes (GEDi-R). We calculated the positive predictive value (PPV) and negative predictive value (NPV) of genetic testing in a population with approximately equal numbers of IRD and AIR patients.

Results: Six patients had clinical features that made distinguishing between IRDs and AIR on a clinical basis difficult and were sent for genetic testing: four women and two men with a mean age of 59.5 years. In two of these six patients, genetic diagnoses were made based upon the identification of known pathogenic variants in the common IRD genes USH2A and RHO. Two patients had variants of unknown significance within genes associated with IRDs, and the other two had no relevant genetic findings. Given the 60% sensitivity and 3% false positive rate for GEDi-R testing and assuming a 50% pre-test probability of having an IRD, the PPV for GEDi-R for detecting IRD is 95.2% and the NPV is 70.8%.

Conclusions and importance: In patients for whom the differential diagnosis of AIR and IRDs is unclear based on clinical information, genetic testing can be a valuable tool when it identifies an IRD, sparing the patient unnecessary immunosuppressive treatment. However, the test has a low NPV so a negative genetic testing result does not confidently exclude IRD as the true diagnosis.

Keywords: Autoimmune retinopathy; Cancer associated-retinopathy; Genetic testing; Inherited retinal degeneration.

Fig. 1

Imaging for patient GT-01 where GEDi-R testing returned positive for known pathogenic mutations in USH2A. Wide field fundus photographs of the right (A) and left (B) eyes show arteriolar attenuation and areas outer retinal atrophy. Wide-field fundus autofluorescence of the right (C) and left (D) eyes show hypoautofluorescent areas corresponding to the areas of outer retinal atrophy in the fundus photographs. E and F: Optical coherence tomography of the macula of the right (E) and left (F) eyes shows pericentral loss of photoreceptor bands.

Fig. 2

Imaging for patient GT-02 where GEDi-R testing returned positive for a known pathogenic mutation in RHO. Wide field fundus photographs of the right (A) and left (B) eyes scattered areas of peripheral pigment loss/drops out. Wide-field fundus autofluorescence of the right (C) and left (D) eyes show some areas of hypoautofluorescence corresponding to areas of RPE loss in the nasal mid-periphery of the left eye. E and F: Optical coherence tomography of the macula of the right (E) and left (F) eyes shows no abnormalities.