A homozygous NRL variant (c.339C>G; p.Try113*) underlies enhanced-S-cone syndrome in the United Arab Emirates and is associated with an electronegative electroretinogram.

INTRODUCTION: Enhanced S-cone syndrome (ESCS) is usually from biallelic pathogenic variants in NR2E3 (nuclear receptor subfamily 2 group E member 3). A less common cause is biallelic pathogenic variants in NRL (neural retina leucine zipper). When recordable, the ESCS electroretinogram (ERG) is pathognomonic. The diagnostic ERG features of ESCS do not include an electronegative waveform. The purpose of this study is to characterize ESCS in the United Arab Emirates (UAE).

METHODS: Retrospective case series of patients diagnosed with ESCS at the Ocular Genetics Clinic of Cleveland Clinic Abu Dhabi (2016-2023, inclusive) who underwent confirmatory genetic analysis (of NR2E3 and, if negative, of NRL).

RESULTS: Ten children (6 families) were identified. One child was homozygous for NR2E3: c.932G>A; p.Arg311Gln. The other 9 children (5 families) were homozygous for NRL: c.339C>G; p.Try113*. Seven children (4 families) had electroretinograms (ERGs), all of which were consistent with ESCS. Six of these children had an electronegative waveform, and they were all homozygous for the specific NRL variant. The child who did not have an electronegative waveform was homozygous for the NR2E3 variant. A literature review for published recordable ERGs in ESCS revealed additional NRL-related cases with an electronegative waveform but no NR23-related cases with an electronegative waveform.

CONCLUSIONS: NRL-related ESCS, related to homozygosity for NRL: c.339C>G; p.Try113*, is recurrent in the UAE and likely represents founder effect. The associated ERG includes an electronegative waveform. This finding may be a way to clinically distinguish NRL-related ESCS from NR2E3-related ESCS.