[Clinical and genetic analysis of a patient with unilateral Pigmented paravenous retinochoroidal atrophy and Retinitis pigmentosa in the contralateral eye related to CRB1 gene variant].

Objective: To explore the clinical phenotype, genotype and genetic characteristics for a patient with unilateral Pigmented paravenous retinochoroidal atrophy (PPRCA) and Retinitis pigmentosa (RP) in the contralateral eye.

Methods: A PPRCA pedigree which had presented at the Department of Medical Genetics of the Eye Hospital of Wenzhou Medical University in August 2021 was selected as the study subject. Clinical data of the family members were collected. The proband underwent wide-field fundus photography, wide-field autofluorescence, full-field electroretinogram (ff-ERG), visual field testing, optical coherence tomography (OCT), and fundus angiography (FFA and ICGA). Blood samples were collected from the proband and family members (parents and two sisters), and buccal mucosal cells were collected from the proband's daughter, and genomic DNA was extracted for each family member. Whole exome sequencing (WES) was performed on the proband. Candidate variants were verified using Sanger sequencing and pathogenicity analysis. This study was approved by the Medical Ethics Committee of the Eye Hospital of Wenzhou Medical University (Ethics No. 2019-134).

Results: Wide-angle fundus photography and autofluorescence showed that the right eye was consistent with PPRCA and the left eye with RP. OCT showed that the outer layer of the fovea was intact in the right eye, while disorganized outer segment was found in the fovea of the left eye, and outer segment atrophies outside the fovea were found in both eyes. The amplitudes of ff-ERG decreased significantly in both eyes, and the amplitudes in right eye were slightly higher than those of the left eye. Visual field showed a paracentral arcuate scotoma in the right eye and severe centripetal contraction in the left eye. FFA showed hyperfluorescence in the retinal vein distribution area caused by atrophy of retinal pigment epithelium of the right eye and hypofluorescence related to bone spicule pigmentation, in addition with mottled hypofluorescence of choroid in the left eye. ICGA showed mild paravenous retinochroidal atrophy of the right eye and diffuse choroid capillaries atrophy in the middle and peripheral area of the left eye. WES revealed that the proband had a heterozygous c.2234C>T (p.Thr745Met) variant of the CRB1 gene. Sanger sequencing confirmed that the proband and family members except the father of the proband carried the same CRB1 gene variant. Based on the criteria and guidelines for the classification of genetic variation and related consensus from the American College of Medical Genetics and Genomics (ACMG), this variant was classified as pathogenic (PM3_VeryStrong+PM1+PM2_Supporting +PP3).

Conclusion: The heterozygous c.2234C>T (p.Thr745Met) variant of the CRB1 gene may underlay the unilateral PPRCA with contralateral eye RP in this proband. Above findings have enriched the mutational spectrum of the CRB1 gene.