Genetic Spectrum of Negative Electroretinograms in a Predominantly Pediatric Cohort of 177 Patients

The purpose of this study was to elucidate the common and rare genetic causes of negative electroretinograms (nERGs) and their association with systemic disease and with myopia in a predominantly pediatric cohort.

Patients underwent electroretinogram (ERG) testing at the Hospital for Sick Children (Toronto) between 2007 and 2023. Negative ERG was defined as b/a amplitude of <1 to a dark-adapted 3.0 and/or 10.0 cd*s*m-2 stimulus. Genetic testing results were reanalyzed using American College of Medical Genetics guidelines. Genes accounting for <2.5% of cases were defined as rare.

Of 4347 ERGs performed, 293 (6.7%) cases had nERGs. Among these, 276 (94.1%) were classified as inherited; 193 had genetic testing. Of these, 177 (91.7%) had an established genetic diagnosis involving 41 genes. Major phenotypes included congenital stationary night blindness (CSNB, 55.4%), retinoschisis (18.6%), and photoreceptor dystrophies (17.5%). Both common (CACNA1F, RS1, TRPM1, NYX, and IDUA) and rare genetic associations were identified. Among patients with CSNB, postsynaptic ON-bipolar genes were associated with high myopia, increasing refractive error by -6.12 diopters (D). Collectively, rare causes affected the same number of cases as CACNA1F, the most frequently associated gene (27.7% each). Genetic etiology varied (23 genes; 31 cases) among photoreceptor dystrophies causing nERG. Systemic disease affected 31 cases. Five novel genetic associations (ABHD12, AP3B2, OAT, PCDH15, and PDE6A) were found.

This study expands the genetic spectrum underlying nERGs, confirming prior associations and identifying five novel genes associations. We provide evidence for the role of ON-bipolar pathway in myopia development. In photoreceptor dystrophies, nERGs rarely occur and likely represent a transient epiphenomenon independent of the underlying gene or mechanism.