Comparison of The Results of Sponsored Genetic Testing Panels for Inherited Retinal Diseases.

Background/Objectives: Gene therapy's emergence has made molecular diagnosis for inherited retinal diseases clinically significant. Free genetic testing panels have improved testing access in clinical practice, yet the interpretation of results, especially variants of unknown significance (VUS), remains challenging and requires expertise. This study shares our experience in utilizing sponsored IRD panel tests by Invitae and Blueprint Genetics (BG), reporting their positivity rates, and comparing their reclassification of variants through amendments. Methods: This retrospective study analyzed genetic test reports from patients who underwent testing via Invitae or BG panels. A positive test was determined if there was a pathogenic mutation in an autosomal dominant gene, two pathogenic mutations in an autosomal recessive gene, or a pathogenic mutation in an X-linked gene in a male patient. Results: The testing positivity rates were 34.9% for Invitae (n = 109) and 42.1% for BG (n = 107). Invitae had more pathogenic variants per report (0.87 vs. 0.58 variants, p = 0.0038) and issued more amendments than BG (0.54 vs. 0.03 amendments; p < 0.01). Of the Invitae variant classification changes, 66.2% switched a VUS to benign. In the BG group, 75% of variant reclassifications changed a VUS to pathogenic. As a result of the Invitae amendments, 88% did not change the overall report result. Conclusions: While free-of-charge genetic testing panels offer valuable insights for diagnosing IRD, limitations such as low diagnostic yield and variant classification discrepancies persist between Invitae and BG. VUS should not be considered pathogenic in the clinical decision-making process. Careful interpretation of genetic testing is required.

Association of prepregnancy body mass index and gestational weight gain on severity of optic nerve hypoplasia.

BACKGROUND: Optic nerve hypoplasia (ONH) is a birth defect of unknown etiology and a leading cause of visual impairment in developed countries. Recent studies suggest that factors of deprivation and exposures of poor nutritional status, such as lower gestational weight gain (GWG), may be associated with increased risk of ONH. The present study describes the prenatal features of mothers of ONH cases, including prepregnancy BMI and GWG, and the associations with clinical features of disease severity. METHODS: Retrospective study of prenatal records for cases of ONH enrolled in a research registry. Prepregnancy BMI and GWG were compared to maternal characteristics and clinical findings of ONH severity including bilaterality, hypopituitarism, and neuroradiographic abnormalities. RESULTS: Compared to population-based normative data of births in the United States, mothers of ONH cases (n = 55) were younger (23.3 vs. 25.8 years; p = 0.03), with higher incidence of inadequate GWG (34.0% vs. 20.4%; p = 0.03) predominantly in the first and second trimesters. The presence of major brain malformations was associated with younger maternal age (21.6 [IQR 19.4, 24.7] vs. 24.9 years [IQR 22.1, 28.5] [p = 0.02]), primiparity (44.1% vs. 13.3%; p = 0.05) and decreased prepregnancy BMI (20.9 kg/m2 [19, 22.5] vs. 25.5 kg/m2 [21.3, 28.2]; p < 0.01). CONCLUSION: Decreased prepregnancy BMI and inadequate GWG correlated with clinical features of ONH severity, specifically bilateral disease and presence of major brain malformations.

Implementation of a pilot teleretinal screening protocol for hydroxychloroquine retinopathy in a Los Angeles County safety net clinic.

INTRODUCTION: This study aimed to determine whether teleretinal screening for hydroxychloroquine retinopathy (HCQR) improves clinical efficiency and adherence to recommended screening guidelines compared to face-to-face screening among patients in a large safety net medical system. METHODS: In this retrospective cohort study of a consecutive sample of 590 adult patients with active HCQ prescriptions seen in the outpatient ophthalmology clinic at Los Angeles County + University of Southern California Medical Center from 1 September 2018 to 25 November 2019, 203 patients underwent technician-only tele-HCQR screening (THRS), and 387 patients underwent screening with traditional face-to-face visits (F2FV) with an eye-care provider. Data on clinic efficiency measures (appointment wait time and encounter duration) and adherence to recommended screening guidelines were collected and compared between the two cohorts. RESULTS: Compared to F2FV, the THRS cohort experienced significantly shorter median (interquartile range) time to appointment (2.5 (1.5-4.6) vs. 5.1 (2.9-8.4) months; p < 0.0001), shorter median encounter duration (1 (0.8-1.4) vs. 3.7 (2.5-5.2) hours; p < 0.0001) and higher proportion of complete baseline screening (102/104 (98.1%) vs. 68/141 (48.2%); p < 0.001) and complete chronic screening (98/99 (99%) vs. 144/246 (58.5%); p < 0.001). DISCUSSION: A pilot THRS protocol was successfully implemented at a major safety net eye clinic in Los Angeles County, resulting in a 50.9% reduction in wait times for screening, 72.9% reduction in encounter duration and 49.9% and 40.5% increases in proportions of complete baseline and chronic screening, respectively. Tele-HCQ retinal screening protocols may improve timeliness to care and screening adherence for HCQR in the safety net setting.

Two cases of uveitis associated with severe transaminitis during a Rickettsia typhi outbreak in Los Angeles County.

PURPOSE: To report the clinical presentation, multimodal imaging, and management of two patients with Rickettsia typhi infection who presented with transaminitis and bilateral uveitis. OBSERVATIONS: We report two cases of murine typhus-associated uveitis in the setting of a Rickettsia typhi outbreak in Los Angeles County. In case 1, a 29-year-old Hispanic female presented with scotoma of the right eye and bilateral floaters after 2 weeks of persistent fevers, maculopapular rash, and arthralgia. Clinical examination and optical coherence tomography (OCT) revealed vitreous cell and scattered white spots in both eyes at the level of the inner retina, and a cotton wool spot inferiorly in the left eye. Multiple hyperautofluorescent spots were seen on widefield fundus autofluorescence (FAF). Retinal vascular leakage and optic disc hyperfluorescence were visualized on widefield fluorescein angiography (FA). These findings were concerning for a white dot syndrome (WDS). The patient was started on oral prednisone 30 mg daily. Serologic testing during the convalescent phase returned positive for R. typhi infection and she was started on doxycycline. 3 weeks later, she reported complete resolution of scotoma and significant improvement of bilateral floaters.In the second case, a 42-year-old Hispanic male presented with sudden bilateral increased floaters and blurry vision after 12 days of persistent fever and headache. Clinical examination revealed trace flare with 1+ cell in the anterior chamber, 1+ vitreous cell, and multiple white dots in both eyes at the level of the inner retina. FAF showed scattered hyperautofluorescent spots in both eyes. FA demonstrated late retinal vascular leakage with bilateral hyperfluorescent optic discs. He was started on oral prednisone 40mg, prednisolone acetate 1% drops, and cyclopentolate 1% drops daily. 2 weeks later, serologic titers returned positive for murine typhus and he was started on doxycycline with gradual taper off of steroids. He subsequently had complete resolution of floaters, blurry vision, and the inner retinal white spots. CONCLUSIONS AND IMPORTANCE: Murine typhus-associated uveitis may present with scotoma and increased floaters in the setting of persistent fevers and transaminitis, with pre- or inner retinal white spots seen on fundus examination. Ophthalmologists may aid in prompt diagnosis and initiation of antibiotic therapy, which can shorten the course of the disease and in turn, reduce the risk of severe complications.