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.
Humans ; Electroretinography ; Exome Sequencing ; Eye Proteins/genetics* ; Membrane Proteins/genetics* ; Mutation ; Nerve Tissue Proteins/genetics* ; Pedigree ; Phenotype ; Retinitis Pigmentosa/genetics* ; Tomography, Optical Coherence ; Retinal Degeneration ; Eye Diseases, Hereditary

OBJECTIVE: To explore the clinical phenotype and genetic characteristics in two children with Knobloch syndrome (KNO) due to variants of COL18A1 gene. METHODS: Two children presented at the Genetic Eye Disease Clinic of the Eye Hospital of Wenzhou Medical University in October 2023 for ocular lesions were selected as the study subjects. Relevant clinical data and peripheral venous blood samples were collected from the children and their parents. Following genomic DNA extraction, whole-exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of the family members. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2021-212-K-185). RESULTS: Both children exhibited characteristic ocular features of KNO including nystagmus, high myopia, and leopard spot fundus. Additionally, child 1 also presented with congenital occipital bone dysplasia and occipital encephalocele, while child 2 was diagnosed with vitreoretinochoroidopathy and bilateral high myopia. WES has identified compound heterozygous variants of the COL18A1 gene in both children, including a c.3013+3A>C splice-site variant and a c.2743C>T (p.Arg915Ter) nonsense variant in child 1, and a novel c.1702-1G>A splice-site variant and a c.3836C>T (p.Ser1279Leu) missense variant in child 2. A comprehensive literature review has identified 63 domestic and international articles involving 167 patients with KNO whom can be classified into three subtypes, with KNO type I being the most common and caused by pathogenic variants in the COL18A1 gene. Both probands in this study were children with KNO type I. Analysis of the genotype-phenotype correlations and population distribution characteristics revealed that the KNO patients exhibited significant clinical and genetic heterogeneity, along with a broad geographic distribution, with a relatively greater number of cases reported in Brazil and China. and a broad geographic distribution, with the highest numbers reported in Brazil and China. While no significant difference in genotype distribution was observed between Chinese and non-Chinese patients, phenotypic disparities were noted, with the non-Chinese cohort showing significantly higher rates of retinal detachment and developmental delay (P < 0.05), whereas Chinese patients exhibited a greater proportion of macular hypoplasia (P < 0.05). CONCLUSION The main clinical manifestations of KNO include high myopia, vitreoretinal dystrophy, and occipital encephalocele. The novel c.1702-1G>A splice-site variant identified in the COL18A1 gene has expanded the mutational spectrum of KNO type I and provided valuable insights for genetic diagnosis, counseling, and clinical management of the disease.
Humans ; Retinal Detachment/congenital* ; Male ; Female ; Child ; Encephalocele/genetics* ; Exome Sequencing ; Collagen Type XVIII/genetics* ; Phenotype ; Retinal Degeneration/genetics* ; Mutation ; Child, Preschool