Reclassification of a novel <i>NR2E3</i> variant as likely pathogenic: a case report of autosomal recessive RP37 in siblings

<i>NR2E3</i> is a nuclear orphan receptor essential for photoreceptor development. Variants in the <i>NR2E3</i> gene are associated with autosomal recessive retinitis pigmentosa 37 (RP37) and enhanced S-cone syndrome (ESCS). We report a novel <i>NR2E3</i> variant in a family with RP37, aiming to clarify pathogenicity through clinical and genetic evaluation. The proband, a 26-year-old woman, experienced childhood-onset nyctalopia and progressive vision loss. Fundus exam revealed mid-peripheral pigment clumps and parafoveal depigmentation. Fundus autofluorescence showed widespread hypo-autofluorescent lesions; spectral-domain OCT identified outer nuclear layer thinning and ellipsoid zone loss. Full-field electroretinography confirmed severely diminished scotopic and photopic responses. Her 23-year-old sister had milder pigmentary changes and cystoid macular edema, while their 20-year-old brother's phenotype was less pronounced. All three siblings were homozygous for a novel missense variant in <i>NR2E3</i> (NM_014249.4:c.352 G > C; p.Val118Leu), located within the DNA-binding domain. Both parents were heterozygous carriers. A previously reported variant affecting the same codon but resulting in a different amino acid change, along with its elevated allele frequency in East Asian populations, suggests a founder effect and supports its pathogenic potential. This report supports reclassifying <i>NR2E3</i> c.352 G > C (NM_014249.4) as likely pathogenic. A comprehensive genotype-phenotype analysis remains essential for advancing our understanding of <i>NR2E3</i>-associated retinal dystrophies.