Expanding the clinical spectrum of recessive CRX-associated retinal disease: an early-onset retinal dystrophy phenotype

Abstract Objective To characterize the clinical and genetic findings in three affected siblings from a consanguineous family with a novel homozygous CRX variant and an early-onset retinal dystrophy (EORD) phenotype, and to review previously reported cases of recessive CRX -associated retinal disorders. Methods Comprehensive ophthalmic examinations, including visual acuity testing, fundus photography, optical coherence tomography, and full-field electroretinography when available, were performed in all participants. Whole-exome sequencing (WES) was carried out on the affected individuals, followed by variant validation and familial segregation analysis. Previously reported biallelic CRX variants and their associated phenotypes were compiled from the literature for comparative analysis. Results WES identified a novel homozygous missense variant in CRX (NM_000554.6:c.158 A > G; p.Glu53Gly) located within the homeobox domain. Segregation analysis in this consanguineous family confirmed homozygosity in all three affected siblings and heterozygosity in two unaffected siblings, consistent with autosomal recessive inheritance. Affected individuals exhibited an EORD phenotype characterized by early visual decline, macular atrophy, peripheral pigmentary changes, and severe outer retinal atrophy. Review of previously reported cases revealed that recessive CRX variants are extremely rare, with most affected individuals presenting with Leber congenital amaurosis or retinitis pigmentosa phenotypes. Conclusion This study expands the clinical spectrum of recessive CRX -associated retinal disease by identifying an EORD phenotype caused by a homozygous CRX variant. These findings underscore the functional importance of the homeobox domain and highlight the need for further studies to clarify genotype–phenotype correlations.