Variants in FDXR reportedly cause autosomal recessive auditory neuropathy and optic atrophy, expanding to retinal dystrophy. This study aimed to further clarify associated phenotypes. FDXR variants were selected from our in-house whole-exome sequencing dataset of 6397 families with different eye conditions. The clinical data of the identified patients were summarized. Biallelic pathogenic or likely pathogenic FDXR variants were identified in 11 unrelated patients, including 14 missense variants of which 10 were novel. Fundus observation showed complete optic disc pallor, silver wiring or severe attenuation of retinal vessels, and varying degrees of generalized retinal degeneration. Before the detection of FDXR variants, four patients were clinically diagnosed as congenital amaurosis due to the presence of nystagmus a few months after birth, while seven were diagnosed as early-onset severe retinal dystrophy due to the presence of nyctalopia and/or poor vision in early childhood. Biallelic FDXR variants are a frequent cause of congenital or early-onset severe retinal dystrophy, especially for patients with severe optic atrophy and retinal dystrophy in early childhood.

(1) Background: NR2E3 encodes a nuclear receptor transcription factor that is considered to promote cell differentiation, affect retinal development, and regulate phototransduction in rods and cones. This study aimed to analyze the clinical characteristics and observe the prognosis of autosomal dominant retinopathy (ADRP) and autosomal recessive retinopathy (ARRP) associated with NR2E3; (2) Methods: NR2E3 variants were collected from our exome sequencing data and identified per the American College of Medical Genetics and Genomics criteria. Data from our cohort and a systemic literature review were conducted to explore the NR2E3 variants spectrum and potential genotype-phenotype correlations; (3) Results: Nine pathogenic variants/likely pathogenic variants in NR2E3, including five novel variants, were detected in eight families (four each with ADRP and ARRP). Follow-up data showed schisis/atrophy in the macula and retinal degeneration initiation around the vascular arcades with differences in ADRP and ARRP. A systemic literature review indicated patients with ADRP presented better visual acuity (p < 0.01) and later onset age (p < 0.0001) than did those with ARRP; (4) Conclusions: Macular schisis and retinal degeneration around vascular arcades may present as the prognosis of NR2E3-retinopathy, dominant, or recessive. Our data might further enrich our understanding of NR2E3 variants and associated inherited retinopathy.

UBAP1L is a newly discovered gene related to recessive inherited retinal degeneration (IRD) with an unknown pathogenic mechanism. This study aims to investigate whether biallelic pathogenic variants in UBAP1L contribute to the unsolved cases in Chinese IRD families and to explore the impact of the Ubap1l genetic defect in a mouse model. Next-generation sequencing was used to detect variants in families with unknown pathogenic variants. Biallelic variants in UBAP1L, evaluated through multistep bioinformatic analysis, comparison across multiple databases, and related phenotype analysis based on thoroughly reviewed clinical data, were confirmed by Sanger sequencing and cosegregation analysis. The expression profiles of UBAP1L in human and Ubap1l in mouse were demonstrated using quantitative RT-PCR and RNAscope. Phenotype and photoreceptor morphology were analyzed in the Ubap1l knockout mouse model. Biallelic novel pathogenic variants in UBAP1L were exclusively detected in two unrelated families with retinitis pigmentosa (RP), including a homozygous c.[278C>A;280dup]/p.[(T93K;I94fs)] variant in one family and compound heterozygous variants (i.e., c.[278C>A;280dup]/p.[(T93K;I94fs)] and c.1051A>G/p.M351V) in the other family. Quantitative RT-PCR showed that UBAP1L was highly expressed in human and mouse retina. RNAscope analysis revealed that UBAP1L was specifically expressed in the outer nuclear and inner segments in the human and mouse retina. Notably, in the human retina, UBAP1L was more highly expressed in cones, with low but detectable expression in the RPE, whereas this expression pattern was not observed in the mouse retina. Ubap1l knockout mice exhibited mottled retinal degeneration, impaired photoreceptor function, and deformation of the rod outer segments. For the first time, biallelic pathogenic variants in UBAP1L were reported to explain the genetic defect among East Asian families with RP. The expression profile and precise localization of UBAP1L were demonstrated. A Ubap1l knockout mouse model replicating key hallmarks of IRD was established. These findings provide valuable insights into the essential role of UBAP1L in maintaining photoreceptor function and offer potential avenues for therapeutic development targeting IRD.