The Value of Electroretinography in Identifying Candidate Genes for Inherited Retinal Dystrophies: A Diagnostic Guide

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TL;DR

This review demonstrates that full-field electroretinography (ffERG) is a critical tool for localizing retinal dysfunction in inherited retinal dystrophies (IRDs), particularly by identifying electronegative waveforms that indicate inner retinal diseases. Distinct ERG patterns help differentiate conditions such as congenital stationary night blindness, X-linked retinoschisis, and cone-rod dystrophies, guiding targeted genetic testing. Clinically, integrating ERG with multimodal imaging and family history enables precise diagnosis, which is essential for prognosis, genetic counseling, and emerging gene therapies.

Full summary

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**Background:** Inherited retinal dystrophies (IRDs) are a genetically heterogeneous group of disorders caused by mutations in genes affecting photoreceptors, bipolar cells, or the retinal pigment epithelium. Accurate diagnosis is crucial for prognosis, genetic counseling, and eligibility for gene-based therapies. While genome sequencing costs are decreasing, whole-genome or whole-exome sequencing can generate false positives, incidental findings, and interpretation challenges. Therefore, narrowing the differential diagnosis through clinical assessment, multimodal imaging, and functional testing is preferred before targeted gene sequencing. Full-field electroretinography (ffERG) is a non-invasive electrophysiological test that measures the massed electrical response of the retina to light stimuli, allowing assessment of rod, cone, and bipolar cell function. This review aims to provide a diagnostic guide for using ffERG to identify candidate genes for monogenic IRDs that exhibit distinct ERG patterns.

**Methods:** The authors conducted a narrative review of the literature on IRDs with characteristic ERG features. They describe the physiological basis of ERG, including the origins of the a-wave (photoreceptor hyperpolarization) and b-wave (bipolar cell depolarization). The review focuses on monogenic IRDs that display distinct ERG patterns, including those with electronegative waveforms (b-wave smaller than a-wave) and other unique features. For each disease, the pathophysiology, clinical presentation, fundus and imaging findings, inheritance patterns, and specific ERG characteristics are discussed, along with the associated genes. The authors also address technical considerations, variability, and the importance of integrating clinical findings with ERG.

**Key Results:** The review identifies several IRDs with distinctive ERG patterns: - **Electronegative DA ERG (b-wave < a-wave):** This pattern indicates post-receptoral dysfunction (bipolar cells or photoreceptor-bipolar synapse). Diseases include: - **Congenital Stationary Night Blindness (CSNB):** Three types with normal fundus: Riggs-type (flat scotopic a-wave, normal photopic; genes: *GNAT1, PDE6B, RHO, SLC24A1*), complete cCSNB (extinguished DA 0.01 ERG, electronegative DA 3/10 ERG, preserved photopic b-wave with sharp rise; genes: *NYX, GRM6, LRIT3, TRPM1, GPR179*), and incomplete iCSNB (reduced DA 0.01 ERG, electronegative DA 3/10 ERG, reduced photopic b-wave with bifid 30 Hz peaks; genes: *CACNA1F, CABP4, CACNA2D4*). - **X-linked Retinoschisis (XLRS):** Caused by *RS1* mutations; fundus shows spoke-wheel maculopathy; OCT reveals cystoid macular edema; ERG shows reduced scotopic response and electronegative DA 3 ERG (not required for diagnosis). - **Cone-Rod Dystrophy:** *CRX* mutations (autosomal dominant) cause progressive cone-rod dystrophy with electronegative DA 3/10 ERG; similar features seen with *RAX2, GUCY2D, PRPH2*. - **Not characteristic of electronegative DA ERG:** - **Fundus Albipunctatus:** *RDH5* mutations; fundus shows white dots sparing fovea; ERG shows recovery of scotopic response after prolonged dark adaptation. - **Enhanced S-cone Syndrome (ESCS):** *NR2E3* mutations; triad of extinguished DA 0.01 ERG, similar waveforms in DA 3/10 and LA 3 ERG, and larger LA 3 a-wave than LA 30 Hz wave; S-cone ERG elevated. - **Cone Dystrophy with Supernormal Rod Response (CDSRR):** *KCNV2* mutations; severely reduced and delayed photopic responses; DA 0.01 ERG reduced and delayed; DA 3.0 ERG shows disproportionately augmented b-wave (supernormal rod response).

**Clinical Implications:** ERG is essential for localizing the dysfunctional retinal layer, which guides targeted genetic testing. This approach reduces costs, avoids incidental findings, and improves diagnostic accuracy. For example, electronegative ERG narrows the differential to inner retinal diseases (CSNB, XLRS, CRX-related cone-rod dystrophy). Distinct ERG patterns also help differentiate conditions with similar fundus appearances (e.g., fundus albipunctatus vs. retinitis punctata albescens; ESCS vs. retinitis pigmentosa). ERG is particularly valuable in young patients or those with nystagmus, where imaging may be challenging. The review emphasizes that ERG should be integrated with personal/family history, fundus imaging, OCT, and autofluorescence for precise diagnosis. Emerging gene therapies (e.g., for *RPE65* mutations) and clinical trials (e.g., for XLRS using AAV.SPR delivery) highlight the need for accurate genetic diagnosis. Limitations include variability, need for expertise, and potential medication effects. Future advancements include handheld ERG devices and machine learning analysis to improve accessibility and interpretation.