Autosomal Recessive NRL Mutations in Patients with Enhanced S-Cone Syndrome

Abstract

Enhanced S-cone syndrome (ESCS) is mainly associated with mutations in the <i>NR2E3</i> gene. However, rare mutations in the <i>NRL</i> gene have been reported in patients with ESCS. We report on an ESCS phenotype in additional patients with autosomal recessive <i>NRL</i> (ar<i>NRL</i>) mutations. Three Moroccan patients of two different families with ar<i>NRL</i> mutations were enrolled in this study. The mutation in the DNA of one patient, from a consanguineous marriage, was detected by homozygosity mapping. The mutation in the DNA of two siblings from a second family was detected in a targeted next-generation sequencing project. Full ophthalmic examination was performed, including best-corrected visual acuity, slit-lamp biomicroscopy, funduscopy, Goldmann kinetic perimetry, optical coherence tomography, fundus autofluorescence, and extended electroretinography including an amber stimulus on a blue background and a blue stimulus on an amber background. One patient carried a homozygous missense mutation (c.508C>A; p.Arg170Ser) in the <i>NRL</i> gene, whereas the same mutation was identified heterozygously in the two siblings of a second family, in combination with a one base-pair deletion (c.654del; p.Cys219Valfs*4) on the other allele. All patients had reduced visual acuity and showed a typical clumped pigmentary retinal degeneration (CPRD). Foveal schisis-like changes were observed in the oldest patient. An electroretinogram (ERG) under dark-adapted conditions showed absent responses for low stimulus strengths and reduced responses for high stimulus strengths, with constant b-wave latencies despite increasing stimulus strength. A relatively high amplitude was detected with a blue stimulus on an amber background, while an amber stimulus on a blue background showed reduced responses. The ar<i>NRL</i> mutations cause a phenotype with typical CPRD. This phenotype has previously been described in patients with ESCS caused by <i>NR2E3</i> mutations, and rarely by <i>NRL</i> mutations. Based on our findings in ERG testing, we conclude that S-cone function is enhanced in our patients in a similar manner as in patients with <i>NR2E3</i>-associated ESCS, confirming previous reports of <i>NRL</i> as a second gene to cause ESCS.