Background The electronegative electroretinogram (ERG)—in which the dark-adapted bright-flash b-wave amplitude falls below the a-wave (b: a ratio < 1.0)—localizes dysfunction to the inner retina or photoreceptor–bipolar synapse. In inherited retinal disease (IRD), this waveform has been associated with a restricted set of genetic etiologies, but the evidence has not been systematically synthesized. Objective To systematically identify and appraise the evidence on genetically confirmed IRD associated with electronegative ERG, characterizing reported gene-specific electrophysiologic patterns, structural correlates, and clinical features. Methods A systematic search of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library was conducted from inception through March 2026, following PRISMA 2020 guidelines. Studies reporting patients with genetically confirmed IRD and electronegative full-field ERG were included. For this review, electronegative ERG was defined quantitatively as a dark-adapted bright-flash b: a amplitude ratio below 1.0 where numerical data were provided; studies using only qualitative descriptors without numerical ratios were included but flagged in sensitivity analysis, as qualitative labelling introduces subjectivity and reduces cross-study comparability. Quality was assessed using Joanna Briggs Institute checklists. Evidence was synthesized narratively, stratified by gene group, because clinical and methodological heterogeneity precluded meta-analysis. Results Eighty-seven studies (approximately 1,250 patients; 23 countries; 1986–2025) met inclusion criteria. The literature was dominated by case reports and small case series (83%), with substantial heterogeneity in ERG protocols and inconsistent ISCEV compliance (documented in 61%). The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2). Electronegative ERG patterns were commonly described across the CSNB and XLRS literature, with the greatest consistency for complete CSNB and KCNV2. Structural imaging correlates showed gene-group specificity, particularly foveal schisis in RS1-associated disease. Evidence for rarer gene associations was limited to isolated case reports. Risk of bias was high across most included studies. These limitations directly inform the confidence ratings assigned to each gene–phenotype association throughout the review. Conclusions Electronegative ERG appears to be a potentially useful phenotypic marker that may help narrow the genetic differential in IRD, particularly for CSNB, XLRS, and KCNV2-associated disease. This utility is most applicable in clinical settings where comprehensive genetic sequencing is not immediately accessible; ERG findings should be interpreted in conjunction with structural imaging and clinical context rather than in isolation. However, the evidence base is constrained by small sample sizes, heterogeneous methodology, likely publication bias, and limited longitudinal data. Importantly, conclusions regarding rarer gene associations should be treated as preliminary, given that they rest on isolated case reports with high risk of bias. Prospective studies with standardized ERG protocols and reporting are needed to validate the diagnostic patterns identified in this review.

Electronegative electroretinography in inherited retinal disease: a systematic review of genotype–phenotype correlations

期刊论文
出版模式：

开放获取
发表日期：

2026年5月9日

查看全文

Ibrahim Taha,
Khalil Huraibat,
Liana Al-Labadi

摘要

Background

The electronegative electroretinogram (ERG)—in which the dark-adapted bright-flash b-wave amplitude falls below the a-wave (b: a ratio < 1.0)—localizes dysfunction to the inner retina or photoreceptor–bipolar synapse. In inherited retinal disease (IRD), this waveform has been associated with a restricted set of genetic etiologies, but the evidence has not been systematically synthesized.

Objective

To systematically identify and appraise the evidence on genetically confirmed IRD associated with electronegative ERG, characterizing reported gene-specific electrophysiologic patterns, structural correlates, and clinical features.

Methods

A systematic search of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library was conducted from inception through March 2026, following PRISMA 2020 guidelines. Studies reporting patients with genetically confirmed IRD and electronegative full-field ERG were included. For this review, electronegative ERG was defined quantitatively as a dark-adapted bright-flash b: a amplitude ratio below 1.0 where numerical data were provided; studies using only qualitative descriptors without numerical ratios were included but flagged in sensitivity analysis, as qualitative labelling introduces subjectivity and reduces cross-study comparability. Quality was assessed using Joanna Briggs Institute checklists. Evidence was synthesized narratively, stratified by gene group, because clinical and methodological heterogeneity precluded meta-analysis.

Results

Eighty-seven studies (approximately 1,250 patients; 23 countries; 1986–2025) met inclusion criteria. The literature was dominated by case reports and small case series (83%), with substantial heterogeneity in ERG protocols and inconsistent ISCEV compliance (documented in 61%). The most frequently reported associations were with genes causing congenital stationary night blindness (NYX, CACNA1F, TRPM1, GRM6, GPR179, CABP4, LRIT3), X-linked retinoschisis (RS1), and cone dystrophy with supernormal rod responses (KCNV2). Electronegative ERG patterns were commonly described across the CSNB and XLRS literature, with the greatest consistency for complete CSNB and KCNV2. Structural imaging correlates showed gene-group specificity, particularly foveal schisis in RS1-associated disease. Evidence for rarer gene associations was limited to isolated case reports. Risk of bias was high across most included studies. These limitations directly inform the confidence ratings assigned to each gene–phenotype association throughout the review.

Conclusions

Electronegative ERG appears to be a potentially useful phenotypic marker that may help narrow the genetic differential in IRD, particularly for CSNB, XLRS, and KCNV2-associated disease. This utility is most applicable in clinical settings where comprehensive genetic sequencing is not immediately accessible; ERG findings should be interpreted in conjunction with structural imaging and clinical context rather than in isolation. However, the evidence base is constrained by small sample sizes, heterogeneous methodology, likely publication bias, and limited longitudinal data. Importantly, conclusions regarding rarer gene associations should be treated as preliminary, given that they rest on isolated case reports with high risk of bias. Prospective studies with standardized ERG protocols and reporting are needed to validate the diagnostic patterns identified in this review.