Mutations in the OPN1LW gene located in X chromosome usually lead to blue cone monochromacy.Variations in OPN1LW gene usually occur in the exon region, but was rare in the intron region.This study was to report a Chinese family with X-linked rod-cone dystrophy associated with a novel OPN1LW gene hemizygotic splicing variation and analyze the clinical phenotype and gene mutation characteristics
A pedigree investigation was performed.The family members clinically diagnosed as rod-cone dystrophy with myopia were enrolled in Henan Provincial People’s Hospital on January 9, 2020.Detailed ophthalmological examination was carried out, and the periphery venous blood was collected for DNA extraction.The target gene sequencing panel PS400 developed by Henan Clinical Research Center for Eye Diseases and whole exon sequencing were used to detect pathogenic mutations.Sanger sequencing and pedigree co-segregation were used to verify variations.The pathogenicity of the novel variation was analyzed based on American College of Medical Genetics (ACMG) Guidelines and online tools SIFT, Polyphen2, Mutation Taster.This study adhered to the Declaration of Helsinki, and the study protocol was approved by the Medical Ethics Committee of Henan Eye Hospital (HNEECKY-2019 ). Written informed consent was obtained from each family member before any medical examination.
The proband was a 5-year-old boy with poor vision, red-green blindness and nystagmus in both eyes.No obvious abnormality in ocular anterior segment was found.The boundary of optic disc was clear and the color was reddish, and the reflection of macular fovea was clearly visible.OCT image showed indistinct reflection of some ellipsoids in macular area of both eyes.The amplitudes of a and b waves of full-field ERG were not recorded in scotopic 0.01 scale and significantly reduced in scotopic 3.0 and photopic 3.0 ERG.The uncle of the proband had a more severe clinical phenotype.Wide-angle fundus photography showed high myopia findings, peripheral retinal atrophy and sporadic black lesions, and autofluorescence examination showed attenuated fluorescence in peripheral retina.No obvious abnormality was found in the middle-peripheral retinal region.The results of two kinds next generation sequencing showed a novel hemizygotic splicing variation c. 112+ 2T>G in the intron of OPN1LW gene and an unreported heterozygous variation c. 1913A>C (p.Y638S) in the SEMA4A gene.The c. 112+ 2T>G mutation further leaded to the sequence change of classic splice donor of intron 1.According to the ACMG guidelines, the pathogenicity score was PVS1+ PM2+ PP1, which was considered as a pathogenic level.
This is the first report of X-linked rod-cone dystrophy associated with OPN1LW gene variation, and this novel variant c. 112+ 2T>G locates in the intron region.This result is different from past knowledge that variations of OPN1LW gene primarily occur in exon.This study expands the mutational spectrum of OPN1LW gene inducing retinal degeneration and the spectrum of clinical phenotype.