NRL-associated autosomal recessive retinopathy: novel variants expanding the phenotype, natural history and a comprehensive literature search.

Background: Neural retina leucine zipper (NRL) is a crucial transcription factor that plays a key role in the development and differentiation of photoreceptor cells. A variant in this gene can cause a retinal phenotype known as Enhanced S cone Syndrome (ESCS). This study presents three novel autosomal recessive (ar) NRL variants and expands the clinical ophthalmic phenotype of NRL-associated retinopathy to include microphthalmia.

Methods: Investigations included electrodiagnostic testing, best corrected visual acuity (BCVA), optical coherence tomography (OCT), ultra-wide field autofluorescence (UWAF), fundus imaging, and visual fields. PubMed, Cochrane library and ClinVar database were used for literature search.

Results: Three patients (P1-3) from 2 different families with novel biallelic NRL variants were reported. P1 had novel homozygous likely-pathogenic NRL variant, p.(Glu86*). Genetic screening of both P2 and P3 identified a second and third novel heterozygous likely pathogenic variants, p.(Leu75Profs *19) and p.(Ser6Alafs *13). Multimodal imaging and functional studies in these patients were consistent with the classical features of ESCS with an additional feature of microphthalmia.

Conclusion: This study expands the genotype and phenotype of NRL-associated retinopathy and compares the ocular phenotype of our cohort with published NRL reports in the literature.